No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.
Uncertain.The recorded classification is uncertain significance.
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.TARDBP encodes TAR DNA-binding protein 43 (TDP-43), an RNA/DNA-binding protein that helps regulate gene transcription, RNA splicing, and the transport and stability of messenger RNA. Mutations in this gene are a cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), and abnormal clumping of TDP-43 protein is a hallmark of several neurodegenerative disorders. TARDBP has no established role in cancer.
The recorded framework is Not recorded. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.
The applied criteria and their strengths are shown as assessed under the stated framework.
Met (Supporting): two independent functional studies show abnormal variant biology — accelerated amyloid formation with ~25% reduced cell viability, and neurodegeneration in patient-derived motor neurons.
Met (Supporting): residue 294 lies in the C-terminal glycine-rich domain where essentially all disease-causing TARDBP missense variants cluster, and the change disrupts this domain.
Met (Supporting): essentially absent from population databases — gnomAD v4.1 allele frequency 3.1e-06 with zero homozygotes.
Met (Supporting): the variant cosegregated with ALS in an affected proband and an affected sibling in a familial case.
Met (Supporting): TARDBP ALS/FTD is a missense-predominant disease gene, and the affected domain is absent from hundreds of control chromosomes.
Met (Supporting): SpliceAI predicts no splice impact (max delta 0.00), far below any splice-altering threshold.
Generic ACMG/AMP 2015 fallback: five supporting pathogenic criteria (PS3, PM1, PM2, PP1, PP2) versus one supporting benign criterion (BP4); no combination threshold is met, so the classification is VUS.
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1: 5 / 1,613,862 alleles. Recorded AF 3.09816e-06. Recorded homozygote count 0.
This variant is present in gnomAD v2.1 (AF= 1.19445e-05; MAF= 0.00119%, 3/251162 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 2.64434e-05; MAF= 0.00264%, 3/113450 alleles, homozygotes = 0); grpmax FAF= 7.03e-06.
Absent from gnomAD-Canada v1.0.
Recorded REVEL score: 0.534. Refer to the recorded PP3/BP4 rationale for interpretation.
8 Pathogenic · 1 Likely pathogenic. ClinVar API review status: criteria provided, multiple submitters, no conflicts.
No standalone functional evidence summary is recorded in evidence_summary.functional.
This variant has not previously been reported in somatic cancers (COSMIC).
This variant does not lie in a statistically significant hotspot.
ACMG/AMP criteria under Not recorded, with the data and sources behind each one.
28 criteria with recorded statuses: 6 met · 7 not met · 9 not assessed · 6 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
No TARDBP CSPEC/VCEP specification is available for this case (vcep_materials.json: note='no cspec url available'; case_summary.json: cspec.found=false), so all five criteria in this group were adjudicated under generic ACMG/AMP 2015 semantics per the final_classification_framework generic_acmg_fallback.
PM1 and PP2 are met at supporting strength based on convergent literature evidence that TARDBP pathogenic variants, including this one, cluster as missense substitutions within the C-terminal low-complexity glycine-rich domain, with the domain-disruption specifically documented for G294V.
PS1 is not_applicable because the reviewed evidence documents only the identical c.881G>T nucleotide variant itself, not an independent different-nucleotide variant converging on the same p.(Gly294Val) protein change.
PM5 is not_assessed because the case's own pm5_candidates.json artifact explicitly skipped automated same-residue candidate harvesting, and no alternate amino-acid substitution at codon 294 itself was identified in the reviewed literature (the nearby G295S substitution is at a different residue).
BP1 is not_met because TARDBP's established disease mechanism for ALS/FTD is missense-driven rather than truncating-variant-driven, the opposite premise required for BP1.
No TARDBP-specific VCEP/CSPEC framework was available, so generic ACMG/AMP criteria were used.
The strongest segregation evidence is one affected sibling carrying the exact p.G294V variant, supporting PP1 at supporting strength.
The available family reports do not document confirmed parental testing or variant-positive unaffected relatives; therefore PS2, PM6, and BS4 are not assessed.
No TARDBP ClinGen VCEP CSPEC is present in this case (cspec.found=false); generic ACMG/AMP PS3/BS3 principles were applied.
PS3 met at supporting strength based on two independent, orthogonal functional studies (in vitro peptide biophysics/cytotoxicity assay and patient-derived iPSC motor neuron model) both showing abnormal biology specific to G294V, though neither meets the rigor threshold (validated benign/pathogenic control panel, isogenic controls, independent replication) needed for strong-level evidence.
BS3 not met: no functional evidence in the bundle shows normal/wild-type-like behavior for this variant.
No CSPEC/VCEP-specific PP3/BP4 gene framework is available for TARDBP in this case (cspec.found=false; vcep_materials.final_classification_framework.found=false, framework_mode='generic_acmg'); generic ACMG/AMP calibrated thresholds were applied.
Variant is a missense substitution (NP_031401.1:p.(G294V)); BP7 (synonymous) is not applicable.
PP3 not met: REVEL 0.534 is below the calibrated PP3_Supporting threshold (>=0.644); BayesDel present but not calibrated/verified for this pipeline and excluded; SpliceAI shows no splice impact and does not support PP3.
BP4 met at supporting strength via the splice-impact path: SpliceAI max delta score = 0.00 indicates no predicted splicing effect. REVEL's 0.534 does not independently meet the BP4_Supporting threshold (<=0.290), so only the SpliceAI evidence is counted, avoiding double counting the same prediction across paths.
No TARDBP-specific VCEP/CSPEC framework was available in the case bundle, so the generic ACMG fallback was used.
Population data do not meet BA1 or BS1 thresholds. PM2 is met at supporting strength under the case's stated non-VCEP rare-frequency threshold. BS2 remains not assessed because healthy-relative genotype, age, and penetrance evidence are insufficient.
No criteria match.
No ClinGen VCEP CSPEC is available for TARDBP (cspec.found=false; framework_mode=generic_acmg), so generic ACMG/AMP PS3 principles apply. Two independent functional studies specifically test p.Gly294Val (G294V) and both show abnormal biology consistent with a pathogenic/gain-of-toxic-function mechanism. PMID:25090004 used a synthetic TDP-43 C-terminal peptide (residues 287-322) bearing G294V and, versus the wild-type-derived peptide, found accelerated beta-sheet/amyloid conversion, increased Thioflavin-T fluorescence, twisted fibril formation, liposome membrane permeabilization, and ~25% reduced N2a cell viability at 72h. PMID:29630989 used patient-derived iPSC spinal motor neurons carrying G294V and found age-dependent neurodegeneration (neuron loss, cytoskeletal/neurofilament abnormalities) and organelle (mitochondria/lysosome) transport deficits versus wild-type control cultures, rescued by D-sorbitol treatment. Both studies support a functional abnormality attributable to this specific variant across two independent, orthogonal experimental systems (biophysical/cell-line peptide assay and patient-derived neuronal model), which is the basis for meeting PS3. Strength is capped at supporting rather than strong because: (1) PMID:25090004 uses a truncated synthetic peptide rather than full-length TDP-43, has only a single wild-type comparator (no additional benign-variant control), and does not report formal statistics for the ~25% viability reduction; (2) PMID:29630989 uses a single patient-derived iPSC line per genotype with no isogenic CRISPR-corrected control, so genetic background cannot be fully excluded as a confounder, and notably shows no TDP43 mislocalization/aggregation, meaning the phenotype does not recapitulate the canonical TDP-43 proteinopathy readout. Neither study reports validation against a panel of known pathogenic and benign TARDBP variants, which is required for a 'well-established' assay per generic ACMG/AMP calibration. No TARDBP/ALS-specific VCEP functional-assay specification exists in this case bundle to formally calibrate strength beyond supporting.
generic_acmg_PS3_supporting_two_independent_orthogonal_assays_without_full_validation
No TARDBP CSPEC/VCEP framework is available (generic ACMG fallback), so PM1 is assessed under generic domain/mutational-hotspot logic. Residue G294 lies within the C-terminal low-complexity, glycine-rich domain of TDP-43, which is the region where essentially all ALS/FTD-associated TARDBP missense variants cluster. Functional domain analysis specifically for this variant (SMART/ProteinPredict) found that G294V disrupts this 41-amino-acid glycine-rich low-complexity domain, splitting it into two smaller glycine-rich segments. Independent reports describe the residue as lying in a 'highly conserved, glycine-rich region' of TDP-43 and as evolutionarily conserved across vertebrate species. This is consistent with a well-established critical functional domain/mutational cluster region for TARDBP missense pathogenicity, supporting PM1 at supporting strength.
Generic ACMG PM1 (critical/functional domain without benign variation) applied in absence of a TARDBP-specific VCEP specification.
Using the case's generic non-VCEP population operating threshold, PM2 is met because the variant is absent or extremely rare in reference populations: gnomAD v4.1 AF 3.09816e-06 with 0 homozygotes, gnomAD v2.1 AF 1.19445e-05 with 0 homozygotes, and absent from gnomAD-Canada v1.0. The highest listed ancestry/subpopulation frequencies remain below 0.1%.
Generic non-VCEP operating threshold: PM2 is met for an absent or very rare variant with population AF <0.1%; zero homozygotes and ancestry-aware review support the assessment.
The TARDBP p.G294V variant was reported in an affected ALS proband and in the proband's affected sister in a familial case, providing cosegregation with disease across an informative sibling relationship. The report does not provide a larger quantified meiosis count or testing of additional relatives, so supporting strength is appropriate.
Generic ACMG/AMP PP1 supports cosegregation of the variant with disease in affected family members; apply at supporting strength here because one affected sibling carrying the exact variant is documented and broader segregation data are limited.
No TARDBP CSPEC/VCEP framework is available, so PP2 is assessed under generic ACMG logic (missense is a common mechanism of disease for the gene, with low rate of benign missense variation). TARDBP-related ALS/FTD is a well-documented missense-predominant disease gene: essentially all established pathogenic TARDBP variants reviewed in this case's evidence (G294V, and comparator G295S, S393L referenced across sources) are missense substitutions clustered in the C-terminal glycine-rich low-complexity domain, and multiple independent case-control cohorts found the affected residue and neighboring residues absent from hundreds of control chromosomes (708, 771, 362 respectively across studies), consistent with low benign missense tolerance in this domain.
Generic ACMG PP2 (missense-predominant disease gene with low benign-missense rate) applied in absence of TARDBP-specific VCEP specification.
SpliceAI (source_registry key 'spliceai') reports a max delta score of 0.00 for NM_007375.4:c.881G>T, i.e. no predicted effect on splicing across donor/acceptor gain/loss, which is far below any threshold associated with a splice-altering effect. This supports BP4 at supporting strength via the splice-impact path, independent of the missense in-silico path. On the missense path, REVEL = 0.534 (source_registry 'revel') does not fall below the ClinGen SVI-calibrated BP4_Supporting threshold of REVEL <=0.290 (Pejaver et al. 2022, PMID 36413997), so REVEL does not independently support BP4; it is simply not used for BP4 here (not double counted). BayesDel = 0.324549 (source_registry 'bayesdel') is not usable for BP4 because no verified published calibration threshold is available to this pipeline. No CSPEC/VCEP-specific PP3/BP4 lookup table exists for TARDBP (framework_mode=generic_acmg), so BP4 is applied under generic ACMG/AMP rules using the calibrated SpliceAI splice-impact evidence alone.
Generic ACMG/AMP BP4: calibrated computational evidence (SpliceAI) predicting no deleterious effect (max delta score = 0.00) supports BP4 at supporting strength via the splice-impact path.
No CSPEC/VCEP-specific PP3/BP4 lookup table is available for TARDBP (cspec.found=false; vcep_materials final_classification_framework.found=false; framework_mode='generic_acmg'), so generic ACMG/AMP calibrated in-silico rules apply. This is a missense variant, NM_007375.4:c.881G>T / NP_031401.1:p.(G294V). REVEL score = 0.534 (source_registry key 'revel'), which falls below the ClinGen SVI-calibrated REVEL PP3_Supporting threshold of >=0.644 (Pejaver et al. 2022, PMID 36413997), so REVEL does not meet the threshold required to apply PP3. BayesDel score = 0.324549 is available (source_registry key 'bayesdel') but per this pipeline's verification status no published, citable calibration threshold for BayesDel is available yet, so it is treated as insufficiently calibrated and cannot be used to apply PP3, regardless of the numeric value. aGVGD is not available in this case bundle (not present). SpliceAI (source_registry key 'spliceai') shows max delta score = 0.00, i.e. no predicted splice impact, which does not support a deleterious computational prediction either. With no calibrated predictor reaching a pathogenic-supporting threshold, PP3 is not met.
Generic ACMG/AMP PP3: requires multiple lines of calibrated computational evidence supporting a deleterious effect; not met when the available calibrated predictor (REVEL) falls below its supporting threshold and no other calibrated predictor is available.
ClinVar contains no exact-variant expert-panel Pathogenic or Likely pathogenic assertion. Its Pathogenic/Likely pathogenic aggregate is based on ordinary laboratory submissions and must not trigger PP5 under the required expert-panel-only rule.
Apply PP5 only for an exact-variant ClinVar expert-panel Pathogenic/Likely pathogenic assertion.
The variant is far below the generic benign allele-frequency threshold of >1%. gnomAD v4.1 reports 5/1,613,862 alleles (AF 3.09816e-06; 0 homozygotes), and gnomAD v2.1 reports 3/251,162 alleles (AF 1.19445e-05; 0 homozygotes).
Generic operating threshold: BA1 requires allele frequency >1%.
The observed population frequency is far below the generic BS1 threshold of >0.3%. gnomAD v4.1 reports AF 3.09816e-06 overall and 3.20154e-05 in the highest listed subpopulation; gnomAD v2.1 reports AF 1.19445e-05 overall and 2.64434e-05 in the highest listed subpopulation.
Generic operating threshold: BS1 requires allele frequency >0.3% in a population where the disease is not expected at that frequency.
The only variant-specific functional data identified (PMID:25090004, PMID:29630989) both demonstrate abnormal biological consequences of G294V (increased amyloidogenicity/cytotoxicity in vitro; age-dependent neurodegeneration and organelle-transport deficits in patient-derived motor neurons) rather than evidence of normal/wild-type-like function. No source in this bundle reports a functional assay showing the variant behaves like wild-type. BS3 is therefore not met.
generic_acmg_BS3_no_normal_function_evidence
BP1 applies to missense variants in genes for which truncating/loss-of-function variants are the primary established disease mechanism. TARDBP-related ALS/FTD is, per the reviewed literature, a missense-predominant disease gene (pathogenic variants cluster as missense substitutions in the C-terminal glycine-rich domain rather than acting via truncation), the opposite premise of BP1. The criterion therefore does not meet its supporting condition for this gene and is scored not_met.
Generic ACMG BP1 (missense in a gene where truncating variants are the primary disease mechanism) applied in absence of TARDBP-specific VCEP specification.
ClinVar contains no exact-variant expert-panel Benign or Likely benign assertion. No BP6 evidence is available under the required expert-panel-only rule.
Apply BP6 only for an exact-variant ClinVar expert-panel Benign/Likely benign assertion.
No confirmed de novo occurrence is documented. The available reports do not establish that both biological parents were tested and lacked the variant, and the available family reports are insufficient to satisfy the de novo criterion.
Generic ACMG/AMP PS2 requires a confirmed de novo variant with maternity/paternity confirmed; this case lacks documented parental testing.
No TARDBP VCEP/gene-specific specification was retrieved, so generic ACMG/AMP is applicable. Multiple reports identify p.Gly294Val in individuals with ALS, including affected relatives, but the available reports do not establish a non-overlapping case series with a matched/control comparison and statistical enrichment. Several Italian reports may represent overlapping ascertainment, and control samples differ between studies; therefore counts cannot be pooled to apply PS4.
Generic ACMG/AMP PS4 requires statistically increased variant prevalence in affected individuals compared with controls; case reports alone, especially when cohort overlap is unresolved, are insufficient.
PM5 requires a different missense change at the same residue (a different amino-acid substitution than Val at codon 294) previously established as pathogenic. The case's own pm5_candidates.json artifact explicitly flagged eligible_for_classic_pm5_search=false with the note 'Unable to confirm classic same-residue PM5 semantics safely; skipping automatic candidate harvesting,' and returned zero candidates. The only nearby residue substitution identified in the literature is p.G295S (PMID:25090004), which is at a different residue (295, not 294) and therefore does not qualify as a PM5 comparator. No alternate amino-acid substitution at codon 294 itself was found in the reviewed evidence.
A presumed de novo occurrence cannot be established from the available evidence. Reports of unaffected parents without documented parental genotyping are insufficient for PM6.
Generic ACMG/AMP PM6 applies only to a presumed de novo variant when parental testing is unavailable but the phenotype and family context support de novo origin; the available reports do not establish that context.
No phenotype for the individual undergoing classification is present in the supplied evidence. Although the literature documents ALS presentations among individuals with p.Gly294Val, PP4 requires the evaluated individual's phenotype to be highly specific for a disease with a single genetic etiology; this case-level requirement cannot be assessed from published variant reports alone.
Generic ACMG/AMP PP4 is evaluated from the phenotype of the individual under assessment; published phenotypes of other variant carriers do not substitute for case-level phenotype specificity.
BS2 cannot be established from the available data. gnomAD reports zero homozygotes but does not provide phenotype, age, or penetrance assessment for individual carriers. The reported homozygous ALS case has healthy parents and eight healthy siblings, but the extracted paper evidence does not establish that these relatives carried the variant in the relevant genotype or that they were sufficiently age-appropriate for a fully penetrant adult-onset ALS assessment.
BS2 requires the variant to be observed in healthy adults for a fully penetrant early-onset disorder, or in healthy individuals in a relevant genotype/context; genotype, age, phenotype, and penetrance must be established.
Non-segregation is not established. One report describes healthy parents and eight healthy siblings in a family with a homozygous affected proband, but the extracted evidence does not document their genotypes, ages at examination, or sufficient phenotype assessment to show that variant-positive unaffected relatives failed to express disease.
Generic ACMG/AMP BS4 requires well-established lack of segregation in affected family members or variant-positive unaffected relatives; unaffected status without genotype and adequate phenotype/age assessment is insufficient.
No qualifying allelic observation is available for BP2. The reviewed reports document affected individuals carrying p.G294V, including one homozygous patient, but do not document a second pathogenic or likely pathogenic variant in trans for a dominant disorder, nor a pathogenic variant in cis with p.G294V. The homozygous report is not evidence of cis/trans occurrence with a different pathogenic allele.
Generic ACMG/AMP BP2: consider only when the variant is observed in cis with a pathogenic variant or in trans with a pathogenic variant in a dominant disorder, with phase adequately established.
No case-level molecular results establish that the evaluated individual has an alternate molecular diagnosis that fully explains the phenotype. Published descriptions of other p.Gly294Val carriers do not provide co-occurrence evidence for this individual.
Generic ACMG/AMP BP5 requires a variant found in a case with an alternate molecular basis for disease; it is not inferred from population or published case observations.
PVS1 (ClinGen SVI PVS1 recommendations, PMC6185798, pvs1_generic_framework) applies only to null variant classes — nonsense, frameshift, canonical ±1/2 splice-consensus, translation-initiation-codon loss, and stop-loss variants — each expected to trigger nonsense-mediated decay or otherwise abolish normal protein function. NM_007375.4:c.881G>T in TARDBP is a missense substitution predicted to produce NP_031401.1:p.(Gly294Val). As a result, no null-variant mechanism (nonsense-mediated decay, truncation, or canonical splice disruption) is triggered by this variant class, so PVS1's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.
deterministic_prefilter: requires_null_variant_class
PS1 requires demonstration that a DIFFERENT nucleotide change produces the identical amino-acid substitution already established as pathogenic. No CSPEC/VCEP is available for TARDBP (framework_mode=generic_acmg, cspec.found=false), so generic ACMG semantics apply. All literature evidence gathered for this case (PMID:19224587, PMID:19236453, PMID:19864664, PMID:21651514, PMID:29630989, PMID:31852254) reports the identical NM_007375.4:c.881G>T variant producing p.(Gly294Val) directly, not an independent nucleotide change converging on the same protein change. No comparator variant (e.g. a different codon-294 nucleotide substitution also yielding Val) was identified in the reviewed sources, so the PS1 premise is not met by this evidence set.
PM3 is not applicable because the available TARDBP evidence supports an autosomal-dominant ALS context rather than an established autosomal-recessive disorder. The homozygous p.G294V proband reported by Corrado et al. is an affected individual with an affected brother, but the report does not establish recessive inheritance or provide a second pathogenic allele in trans; the homozygous state alone does not satisfy PM3 for this dominant disease context.
Generic ACMG/AMP PM3: apply only for recessive disease when the variant is observed in trans with a pathogenic variant or otherwise provides validated biallelic evidence; do not apply solely because the proband is homozygous when the disease mechanism is dominant.
PM4 (Richards et al. 2015, PMID:25741868) applies to protein length changes: in-frame insertions/deletions in a non-repetitive region, or stop-loss variants that extend the protein past the reference stop codon. NM_007375.4:c.881G>T in TARDBP is a missense substitution predicted to produce NP_031401.1:p.(Gly294Val). As a result, no change in protein length occurs, so there is nothing for this criterion to evaluate, so PM4's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.
deterministic_prefilter: requires_stop_loss_or_nonrepeat_indel
BP3 (Richards et al. 2015, PMID:25741868) applies to in-frame insertions/deletions located in a repetitive region without a known function. NM_007375.4:c.881G>T in TARDBP is a missense substitution predicted to produce NP_031401.1:p.(Gly294Val). As a result, the variant does not alter protein length within a repeat region, so there is nothing for this criterion to evaluate, so BP3's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.
deterministic_prefilter: requires_repeat_region_indel
BP7 (Richards et al. 2015, PMID:25741868) is defined for a synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence and the nucleotide is not highly conserved. NM_007375.4:c.881G>T in TARDBP is a missense substitution predicted to produce NP_031401.1:p.(Gly294Val). As a result, the encoded protein sequence is altered, so the criterion's silent-variant premise does not hold regardless of any splicing prediction, so BP7's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.
deterministic_prefilter: requires_synonymous
Every interpreted variant in TARDBP, mapped onto the exon structure of NM_007375.4. Select a row to find it on the plot.
| Protein | Location | Classification | Link |
|---|
| Remaining individuals2 / 62,470 | 3.2e-05 |
| European (non-Finnish)3 / 1,179,880 | 2.5e-06 |
| European (non-Finnish)3 / 113,450 | 2.6e-05 |
This variant is present in gnomAD v4.1 (AF= 3.09816e-06; MAF= 0.00031%, 5/1613862 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 3.20154e-05; MAF= 0.00320%, 2/62470 alleles, homozygotes = 0); grpmax FAF= 6.8e-07.
This variant is present in gnomAD v2.1 (AF= 1.19445e-05; MAF= 0.00119%, 3/251162 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 2.64434e-05; MAF= 0.00264%, 3/113450 alleles, homozygotes = 0); grpmax FAF= 7.03e-06.
Absent from gnomAD-Canada v1.0.
SpliceAI (source_registry key 'spliceai') reports a max delta score of 0.00 for NM_007375.4:c.881G>T, i.e. no predicted effect on splicing across donor/acceptor gain/loss, which is far below any threshold associated with a splice-altering effect. This supports BP4 at supporting strength via the splice-impact path, independent of the missense in-silico path. On the missense path, REVEL = 0.534 (source_registry 'revel') does not fall below the ClinGen SVI-calibrated BP4_Supporting threshold of REVEL <=0.290 (Pejaver et al. 2022, PMID 36413997), so REVEL does not independently support BP4; it is simply not used for BP4 here (not double counted). BayesDel = 0.324549 (source_registry 'bayesdel') is not usable for BP4 because no verified published calibration threshold is available to this pipeline. No CSPEC/VCEP-specific PP3/BP4 lookup table exists for TARDBP (framework_mode=generic_acmg), so BP4 is applied under generic ACMG/AMP rules using the calibrated SpliceAI splice-impact evidence alone.
Generic ACMG/AMP BP4: calibrated computational evidence (SpliceAI) predicting no deleterious effect (max delta score = 0.00) supports BP4 at supporting strength via the splice-impact path.
No CSPEC/VCEP-specific PP3/BP4 lookup table is available for TARDBP (cspec.found=false; vcep_materials final_classification_framework.found=false; framework_mode='generic_acmg'), so generic ACMG/AMP calibrated in-silico rules apply. This is a missense variant, NM_007375.4:c.881G>T / NP_031401.1:p.(G294V). REVEL score = 0.534 (source_registry key 'revel'), which falls below the ClinGen SVI-calibrated REVEL PP3_Supporting threshold of >=0.644 (Pejaver et al. 2022, PMID 36413997), so REVEL does not meet the threshold required to apply PP3. BayesDel score = 0.324549 is available (source_registry key 'bayesdel') but per this pipeline's verification status no published, citable calibration threshold for BayesDel is available yet, so it is treated as insufficiently calibrated and cannot be used to apply PP3, regardless of the numeric value. aGVGD is not available in this case bundle (not present). SpliceAI (source_registry key 'spliceai') shows max delta score = 0.00, i.e. no predicted splice impact, which does not support a deleterious computational prediction either. With no calibrated predictor reaching a pathogenic-supporting threshold, PP3 is not met.
Generic ACMG/AMP PP3: requires multiple lines of calibrated computational evidence supporting a deleterious effect; not met when the available calibrated predictor (REVEL) falls below its supporting threshold and no other calibrated predictor is available.
BP7 (Richards et al. 2015, PMID:25741868) is defined for a synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence and the nucleotide is not highly conserved. NM_007375.4:c.881G>T in TARDBP is a missense substitution predicted to produce NP_031401.1:p.(Gly294Val). As a result, the encoded protein sequence is altered, so the criterion's silent-variant premise does not hold regardless of any splicing prediction, so BP7's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.
deterministic_prefilter: requires_synonymous
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.534. BayesDel score = 0.324549.
8 paper records listed. 6 cited in the classification.
The newly identified missense variations affect evolutionary conserved amino acid residues in all or in most of the seven examined vertebrate species... Three of them (p.G294V, p.G335D, and p.S393L) were predicted to have a deleterious effect on TDP-43 protein structure or function by at least 2 out of the 3 considered prediction programs PolyPhen, SNAP, and PMUT.
Location Results, Mutational Analysis; Table 1; Results, clinical characteristics paragraph
Context Exon 6 sequencing in 385 additional Italian ALS patients within a total cohort of 666 ALS patients; comparison with 771 neurologically healthy Italian controls; family testing and in-silico prediction.
The p.G294V amino acid change was identified in an Italian woman who developed progressive lower limb weakness at the age of 73 (Table 2, patient D)... No positive family history for neurological, cardiological and autoimmune diseases has been reported.
Location Results, paragraph describing patient D; Table 2; Discussion, paragraph describing the two novel mutations
Context TARDBP coding-region sequencing in 314 ALS probands (308 Italian) with comparison to 181 Italian healthy volunteers (362 control chromosomes).
Functional domain analysis from both SMART and ProteinPredict programs predict that this mutation causes the disruption of a low complexity, 41 amino acid glycine rich domain in the C terminus of TDP-43. The G294V mutation is predicted to split the domain into two separate glycine rich regions of 18 and 17 amino acids, separated by a six amino acid gap.
Location Results, mutation-screening and functional-domain-analysis paragraphs; Discussion, first paragraph
Context TARDBP sequencing of all six exons and flanking intronic sequences in 30 familial ALS families and 74 sporadic ALS cases; qPCR copy-number assessment; computational analyses using cross-species alignment, SNAP, PolyPhen, SMART, and ProteinPredict; 354 matched controls (708 control chromosomes) sequenced.
In this study, we try to characterize the structure, amyloid properties, membrane permeabilization ability, and biological properties of clinically-related TDP-43 mutants including G294V (familial mutation) and G295S (sporadic mutation).
Location Introduction; Results, Figures 2, 4, 5, and 6
Context In-vitro biophysical and cell-based assays using a synthetic TDP-43 C-terminal peptide spanning residues 287-322: TEM, CD spectroscopy, FT-Raman, ThT fluorescence, sedimentation/HPLC, liposome leakage, and AlamarBlue viability testing in N2a cells.
Human wildtype and TDP43 S393L and G294V mutant spinal motor neuron cultures were differentiated from patient-derived iPSCs... During aging we detected a dramatic neurodegeneration including neuron loss and pathological neurofilament abnormalities only in TDP43 mutant cultures.
Location Abstract; Materials and Methods, Patient characteristics; Results
Context Patient-derived iPSC lines carrying TARDBP G294V or S393L compared with wild-type controls after differentiation into spinal motor neurons.
Here, we described the first amyotrophic lateral sclerosis patient presenting the c.881 G > T p.G294V TARDBP mutation in homozygous status. The patient belongs to a large pedigree from Morocco. Except for one older affected brother his parents and remaining 8 sibs are referred to be healthy and do not show any neurological sign or symptom.
Location Abstract; Results, Clinical description and Genetic analysis; Discussion
Context Single Moroccan ALS case with TARDBP sequencing, MLPA, array-CGH/SNP analysis, and microsatellite haplotype analysis; comparison with 15 additional heterozygous ALS cases and 3,980 Italian controls.
The p.Gly294Val mutation was observed in two unrelated patients with different clinical manifestations (patient nos 2 and 3; Table 1).
Results, paragraph describing the TARDBP mutations; Table 1, patients 2 and 3
The variant classification approach described in this paper is meant to be applicable to variants in all Mendelian genes whether identified by single gene tests, multi-gene panels, exome sequencing or genome sequencing.
Proposed Criteria for Interpretation of Sequence Variants
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This variant is present in gnomAD v4.1 (AF= 3.09816e-06; MAF= 0.00031%, 5/1613862 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 3.20154e-05; MAF= 0.00320%, 2/62470 alleles, homozygotes = 0); grpmax FAF= 6.8e-07.
This variant is present in gnomAD v2.1 (AF= 1.19445e-05; MAF= 0.00119%, 3/251162 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 2.64434e-05; MAF= 0.00264%, 3/113450 alleles, homozygotes = 0); grpmax FAF= 7.03e-06.
Absent from gnomAD-Canada v1.0.
This variant has been reported in ClinVar as Pathogenic (8 clinical laboratories) and as Likely pathogenic (1 clinical laboratory). (ClinVarID = 21484)
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.534. BayesDel score = 0.324549.
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
This variant does not lie in a statistically significant hotspot.