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 (Moderate): Gly295 lies in the exon-6 glycine-rich C-terminal domain, an established mutational hotspot for TARDBP-related ALS/FTLD.
Met (Moderate): extremely rare in gnomAD v4.1 at 2 of 1,613,954 alleles (AF 1.24e-06), below the 0.1% threshold.
Met (Supporting): missense variants in the exon-6 glycine-rich domain are the established dominant disease mechanism for TARDBP.
No benign criterion marked as applied in the recorded assessment.
VUS: PM1 and PM2 (moderate) plus PP2 (supporting) satisfy no ACMG/AMP pathogenic or benign combining rule.
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1: 2 / 1,613,954 alleles. Recorded AF 1.23919e-06. Recorded homozygote count 0.
This variant is present in gnomAD v2.1 (AF= 7.9628e-06; MAF= 0.00080%, 2/251168 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 1.76286e-05; MAF= 0.00176%, 2/113452 alleles, homozygotes = 0); grpmax FAF= 2.93e-06.
Absent from gnomAD-Canada v1.0.
Recorded REVEL score: 0.501. Refer to the recorded PP3/BP4 rationale for interpretation.
1 Pathogenic. ClinVar API review status: criteria provided, single submitter.
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: 3 met · 8 not met · 12 not assessed · 5 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
PM1 met at moderate strength: p.Gly295Ser falls within the exon-6 glycine-rich/prion-like C-terminal domain of TDP-43, a well-documented mutational cluster region for TARDBP-related ALS/FTLD, supported by multiple independent cohort and structural studies.
PP2 met at supporting strength: TARDBP disease is predominantly missense-driven with clustering in this same domain, consistent with the PP2 gene-mechanism criterion.
BP1 not met: TARDBP disease mechanism is missense-driven, not truncating-driven, so this criterion (built for truncating-mechanism genes) does not apply.
PS1 and PM5 not assessed: no independently confirmed comparator variant (different nucleotide change yielding the same G295S amino acid change for PS1, or a classified pathogenic/likely pathogenic alternate change at residue 295 for PM5) was available; the case's own pm5_candidates.json artifact explicitly withheld automated same-residue candidate generation for this variant.
No TARDBP-specific VCEP/CSPEC framework was retrieved; generic ACMG/AMP rules were used.
The exact-variant literature documents affected probands but provides no confirmed de novo, presumed de novo, cosegregation, or non-segregation evidence for NM_007375.4:c.883G>A (p.Gly295Ser).
No TARDBP-specific ClinGen VCEP/CSPEC framework was found for this case (cspec.found=false, gene_vcep_dir=null); generic ACMG/AMP PS3/BS3 standards, informed by ClinGen SVI PS3/BS3 calibration guidance (Brnich et al. 2019, PMID:31892348), were applied.
Two functional studies address p.(G295S) directly: a cellular GFP-tau-3'UTR reporter assay (PMID:28335005) and a synthetic C-terminal peptide aggregation/toxicity study (PMID:25090004). Both report abnormal effects consistent with a pathogenic direction, but neither includes matched pathogenic/benign control variants in the same assay system, so PS3 cannot be confidently applied at any strength per SVI validation requirements; this is flagged for human review rather than scored.
Because all available functional evidence points toward abnormal (not normal) function, BS3 is not met.
TARDBP has no ClinGen VCEP-specific PP3/BP4 lookup materials in this case (cspec.found=false, vcep_materials.summaries empty, framework_mode=generic_acmg), so generic ACMG/AMP calibrated in silico rules govern this criteria group.
Variant NM_007375.4:c.883G>A / NP_031401.1:p.(Gly295Ser) is a missense substitution within TARDBP coding exon 6; the missense in silico path (REVEL) is the primary applicable computational evidence line, with SpliceAI checked as a secondary splice-mechanism check.
REVEL = 0.501 falls in the intermediate zone between the ClinGen SVI-calibrated BP4_Supporting (<=0.290) and PP3_Supporting (>=0.644) thresholds (Pejaver et al. 2022, PMID 36413997), so it supports neither PP3 nor BP4.
BayesDel = 0.285256 is available but has no pipeline-verified named publication establishing a calibrated threshold, so it is excluded from both PP3 and BP4 per calibration policy.
SpliceAI max delta score = 0.00 predicts no splice impact, which is expected for a variant located well within a large coding exon rather than at a splice junction; this negative result does not independently satisfy BP4 given the inconclusive missense-predictor evidence, and no gene-specific splicing-mechanism rationale for this variant is present in the case bundle.
No Align-GVGD/HCI prior score is available (hci_prior.found=false).
Result: PP3 = not_met, BP4 = not_met; both computational-evidence criteria for this variant are indeterminate rather than pathogenic- or benign-supporting.
No criteria match.
Residue Gly295 lies within the highly conserved, glycine-rich (prion-like/low-complexity) C-terminal domain of TDP-43 encoded by exon 6, which is the established mutational cluster region for TARDBP-related ALS/FTLD. Multiple independent studies describe this exon-6 glycine-rich region as harboring the great majority of known TARDBP disease-associated missense variants, including G294V and G295S identified together in the same cohort, and describe the region generally as a hotspot for ALS-causing substitutions with structural/aggregation consequences. One cohort study found 10 different heterozygous missense mutations in this exon-6 region across 14 patients, underscoring its status as a well-characterized mutational hotspot without established benign variation at this position.
PM1 (generic ACMG/AMP 2015): variant located in a mutational hot spot and/or critical and well-established functional domain without benign variation, applied at moderate strength per no gene-specific VCEP override available for TARDBP.
PM2 is met at moderate strength under the generic non-VCEP operating threshold used for this case. The variant is extremely rare in gnomAD v4.1 (AF 1.23919e-06; 2/1,613,954 alleles; 0 homozygotes), remains below 0.1% in the highest listed population (European non-Finnish AF 1.69510e-06), and is absent from gnomAD-Canada v1.0. An independent clinical sequencing study also reported p.G295S absent from 362 control chromosomes.
Generic ACMG/AMP fallback with the case's non-VCEP PM2 threshold of <0.1% allele frequency; rarity/absence in population controls supports PM2.
TARDBP is a gene in which missense variants are the well-established, dominant disease mechanism for ALS/FTLD (in contrast to loss-of-function mechanisms), with essentially all reported pathogenic TARDBP variants being missense substitutions clustered in the exon-6 C-terminal glycine-rich domain. A representative screening cohort found 10 distinct heterozygous missense mutations in this region across 14 patients, and no source in this bundle documents a low-benign-missense-rate metric contradicting this, supporting PP2 at supporting strength.
PP2 (generic ACMG/AMP 2015): missense variant in a gene that has a low rate of benign missense variation and in which missense variants are a common mechanism of disease.
No VCEP-specific PP3/BP4 lookup exists for TARDBP (framework_mode=generic_acmg, cspec.found=false, vcep_materials empty), so generic ACMG/AMP in silico evidence rules apply. This is a missense variant (NP_031401.1:p.(Gly295Ser)); the missense computational path is primary. REVEL score = 0.501 (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 reach the pathogenic-supporting threshold. BayesDel score = 0.285256 is available (source_registry key 'bayesdel') but per this pipeline's verification status no published, named calibration threshold for BayesDel is confirmed, so it is treated as insufficiently calibrated and not usable for PP3. Align-GVGD/HCI prior data was not found (hci_prior.found=false). SpliceAI predicts no splice impact (max delta score = 0.00; source_registry key 'spliceai'), which does not support a splice-disruption mechanism for PP3 either. No calibrated in silico tool reaches a pathogenic-supporting threshold, so PP3 is not met.
generic_acmg_PP3_computational_supporting
No exact-variant ClinVar expert-panel Pathogenic/Likely pathogenic assertion is present. The available Pathogenic assertions are from OMIM and a single clinical laboratory, neither of which is an expert panel.
Apply only for an exact-variant ClinVar expert-panel Pathogenic/Likely pathogenic classification.
BA1 is not met. The maximum observed allele frequency is 1.23919e-06 in gnomAD v4.1 (2/1,613,954 alleles; highest reported population frequency 1.69510e-06 in European non-Finnish individuals), far below the generic BA1 threshold of >1%.
Generic ACMG/AMP fallback; BA1 threshold >1% allele frequency.
BS1 is not met. The observed population frequencies are far below the generic BS1 threshold of >0.3%; gnomAD v4.1 has AF 1.23919e-06 overall and 1.69510e-06 in the highest listed population, and gnomAD v2.1 has AF 7.9628e-06 overall and 1.76286e-05 in the highest listed population.
Generic ACMG/AMP fallback; BS1 threshold >0.3% allele frequency.
The only functional data identified for p.(G295S) (PMID:28335005 cellular reporter assay; PMID:25090004 synthetic peptide aggregation/toxicity assay) consistently show abnormal, not normal, function relative to wild-type TDP-43/peptide, so there is no evidence supporting a benign functional profile. BS3 is therefore not met.
BP1 applies to missense variants in genes where disease is primarily caused by truncating variants; the opposite is true for TARDBP, where missense variants clustered in the exon-6 glycine-rich domain are the established disease mechanism for ALS/FTLD. BP1 is therefore not met.
BP1 (generic ACMG/AMP 2015): missense variant in a gene for which primarily truncating variants are known to cause disease; not applicable to TARDBP given its missense-driven disease mechanism.
No VCEP-specific PP3/BP4 lookup exists for TARDBP; generic ACMG/AMP rules apply. REVEL score = 0.501 is above the ClinGen SVI-calibrated REVEL BP4_Supporting threshold of <=0.290 (Pejaver et al. 2022, PMID 36413997), placing it in the intermediate/indeterminate zone between the BP4 and PP3 thresholds, so REVEL does not support a benign call either. BayesDel score = 0.285256 is available but has no verified published, named calibration threshold confirmed for this pipeline and is therefore treated as not_available/insufficiently calibrated for BP4, consistent with policy regardless of any recalled cutoff. SpliceAI shows no predicted splice impact (max delta score = 0.00), which is the expected/uninformative baseline result for a variant located deep within the large coding exon 6 of TARDBP (not at a canonical splice junction) and does not independently establish BP4 for a missense variant when the primary missense predictor (REVEL) is inconclusive rather than clearly benign. Because no calibrated in silico tool reaches a benign-supporting threshold, BP4 is not met.
generic_acmg_BP4_computational_supporting
No exact-variant ClinVar expert-panel Benign/Likely benign assertion is present.
Apply only for an exact-variant ClinVar expert-panel Benign/Likely benign classification.
PS1 requires a different nucleotide substitution that produces the identical amino acid change (p.Gly295Ser) and that has already been established as Pathogenic/Likely Pathogenic. No source in this case bundle documents an independent codon change at residue 295 that also yields Ser295 (all identified alternate-codon reports at this residue produce p.Gly295Arg, a different amino acid, which is relevant to PM5 rather than PS1). No such comparator variant was found, so PS1 cannot be evaluated.
No confirmed de novo evidence is documented. The available exact-variant reports describe affected probands with p.G295S but do not document parental testing establishing maternity and paternity or demonstrating absence of the variant in both parents.
Generic ACMG/AMP PS2: confirmed de novo occurrence with confirmed maternity and paternity; no gene-specific specification was available.
No CSPEC/VCEP framework is available for TARDBP (framework_mode=generic_acmg; cspec.found=false), so generic ACMG/AMP PS3 standards apply, which per ClinGen SVI PS3/BS3 recommendations (Brnich et al. 2019, PMID:31892348) require a well-validated assay with established positive/negative (known pathogenic/benign variant) controls and demonstrated correlation to the disease mechanism. Two functional studies report abnormal effects for p.(G295S): PMID:28335005 found that TDP-43-G295S, expressed in HEK-293FT cells with a GFP-tau-3'UTR reporter, significantly suppressed GFP protein expression (though not GFP mRNA), similarly to other ALS/FTLD-related TDP-43 mutants tested in the same experiment; PMID:25090004 found that a synthetic TDP-43 C-terminal peptide (residues 287-322) bearing G295S showed accelerated amyloid fibril formation, increased membrane-disruption (calcein leakage) kinetics, and ~35% reduced N2a cell viability versus wild-type peptide. Neither study reports a pathogenic-variant or benign-variant control set run in the same assay to calibrate abnormal versus normal function, and PMID:25090004 uses an isolated synthetic peptide rather than full-length TDP-43 protein, limiting direct biological relevance to the intact protein's disease mechanism. Given the absence of assay validation with matched controls, this evidence cannot be confidently scored as PS3 at any strength under generic ACMG/SVI standards; human review is needed to judge whether the reporter-suppression and peptide-toxicity data are sufficient for a reduced-strength PS3 call (e.g., PS3_supporting) despite the missing controls.
Exact-variant observations in two reported sporadic ALS patients do not constitute a statistically significant enrichment analysis. The available studies provide neither a matched case-control comparison nor sufficient aggregate case and control counts to establish PS4.
Generic ACMG/AMP PS4: prevalence in affected individuals must be significantly increased compared with controls.
Two literature sources report an alternate missense substitution at the same coding position/residue: p.Gly295Arg (from c.883G>C per Ticozzi et al. 2011, and a differently-numbered c.1017G>C per Gonzalez-Perez et al. 2015, an internal inconsistency in the source citation). However, G295R was observed in only a single sporadic ALS patient in each report, with no functional, segregation, or ClinVar pathogenic/likely-pathogenic classification data provided, and the case-tool's own PM5 candidate harvester explicitly declined to auto-generate same-residue comparators for this variant, flagging inability to confirm classic PM5 semantics safely. Without confirmation that G295R is an independently established Pathogenic/Likely Pathogenic variant, PM5 cannot be met.
The exact-variant literature includes sporadic ALS probands, but it does not establish that p.G295S arose de novo. Without documented parental testing or a credible de novo inference, PM6 cannot be applied.
Generic ACMG/AMP PM6: presumed de novo occurrence without confirmed maternity and paternity; no gene-specific specification was available.
No affected relatives carrying the exact variant and no informative meioses are documented. The available reports describe isolated affected probands rather than cosegregation across a family.
Generic ACMG/AMP PP1: cosegregation with disease in affected family members; no gene-specific specification was available.
The reported phenotype is ALS, but no TARDBP-specific phenotype specification is available and ALS is genetically heterogeneous. The available reports do not establish that the affected individuals had a phenotype highly specific for a TARDBP-related disorder.
Generic ACMG/AMP PP4: patient phenotype or family history must be highly specific for a disease with a single genetic etiology.
BS2 is not assessed. gnomAD reports no homozygotes, but the two observed heterozygous alleles are population observations without documented adult phenotype, age, ascertainment, or reliable disease-status follow-up. Therefore they do not establish that the variant is present in healthy adults in a manner sufficient for BS2, particularly for an incompletely penetrant, late-onset dominant disorder.
Generic ACMG/AMP BS2 requires appropriately documented occurrence in healthy adults; unphenotyped population heterozygotes are insufficient, especially for a late-onset or incompletely penetrant dominant condition.
No unaffected relatives who carry the exact variant, and no adequately informative non-segregation analysis, are documented. The available exact-variant reports therefore provide neither positive nor negative segregation evidence.
Generic ACMG/AMP BS4: lack of segregation in affected family members or presence in unaffected family members; no gene-specific specification was available.
BP2 cannot be established from the available evidence. For a fully penetrant dominant disorder, BP2 requires observation of the tested variant in trans with a pathogenic variant. The bundle reports affected individuals carrying p.G295S but provides no co-occurring pathogenic variant, parental testing, haplotype result, or cis/trans phase information. The absence of such data prevents assessment; it is not evidence that BP2 is met.
Generic ACMG/AMP BP2 definition: for a fully penetrant dominant disorder, apply when the variant is observed in trans with a pathogenic variant. A documented second pathogenic variant and reliable phase evidence are required.
No source documents a molecularly established alternative cause of the relevant disease in an individual carrying TARDBP c.883G>A (p.Gly295Ser).
Generic ACMG/AMP BP5: a variant is found in a case with an alternate molecular basis for disease.
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.883G>A in TARDBP is a missense substitution predicted to produce NP_031401.1:p.(Gly295Ser). 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
PM3 is a recessive allelic criterion requiring the tested variant to be observed in trans with a pathogenic variant in an affected individual. The applicable disease context for TARDBP-related amyotrophic lateral sclerosis/FTD in the case bundle is germline autosomal dominant, and the available case reports describe heterozygous affected individuals without a recessive compound-heterozygous interpretation. PM3 therefore does not apply to this case.
Generic ACMG/AMP PM3 definition: apply only for recessive disorders when the variant is observed in trans with a pathogenic variant in an affected individual. Not applicable in the autosomal-dominant TARDBP disease context.
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.883G>A in TARDBP is a missense substitution predicted to produce NP_031401.1:p.(Gly295Ser). 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.883G>A in TARDBP is a missense substitution predicted to produce NP_031401.1:p.(Gly295Ser). 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.883G>A in TARDBP is a missense substitution predicted to produce NP_031401.1:p.(Gly295Ser). 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 |
|---|
| European (non-Finnish)2 / 1,179,872 | 1.7e-06 |
| European (non-Finnish)2 / 113,452 | 1.8e-05 |
This variant is present in gnomAD v4.1 (AF= 1.23919e-06; MAF= 0.00012%, 2/1613954 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 1.6951e-06; MAF= 0.00017%, 2/1179872 alleles, homozygotes = 0); grpmax FAF= 2.8e-07.
This variant is present in gnomAD v2.1 (AF= 7.9628e-06; MAF= 0.00080%, 2/251168 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 1.76286e-05; MAF= 0.00176%, 2/113452 alleles, homozygotes = 0); grpmax FAF= 2.93e-06.
Absent from gnomAD-Canada v1.0.
No VCEP-specific PP3/BP4 lookup exists for TARDBP (framework_mode=generic_acmg, cspec.found=false, vcep_materials empty), so generic ACMG/AMP in silico evidence rules apply. This is a missense variant (NP_031401.1:p.(Gly295Ser)); the missense computational path is primary. REVEL score = 0.501 (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 reach the pathogenic-supporting threshold. BayesDel score = 0.285256 is available (source_registry key 'bayesdel') but per this pipeline's verification status no published, named calibration threshold for BayesDel is confirmed, so it is treated as insufficiently calibrated and not usable for PP3. Align-GVGD/HCI prior data was not found (hci_prior.found=false). SpliceAI predicts no splice impact (max delta score = 0.00; source_registry key 'spliceai'), which does not support a splice-disruption mechanism for PP3 either. No calibrated in silico tool reaches a pathogenic-supporting threshold, so PP3 is not met.
generic_acmg_PP3_computational_supporting
No VCEP-specific PP3/BP4 lookup exists for TARDBP; generic ACMG/AMP rules apply. REVEL score = 0.501 is above the ClinGen SVI-calibrated REVEL BP4_Supporting threshold of <=0.290 (Pejaver et al. 2022, PMID 36413997), placing it in the intermediate/indeterminate zone between the BP4 and PP3 thresholds, so REVEL does not support a benign call either. BayesDel score = 0.285256 is available but has no verified published, named calibration threshold confirmed for this pipeline and is therefore treated as not_available/insufficiently calibrated for BP4, consistent with policy regardless of any recalled cutoff. SpliceAI shows no predicted splice impact (max delta score = 0.00), which is the expected/uninformative baseline result for a variant located deep within the large coding exon 6 of TARDBP (not at a canonical splice junction) and does not independently establish BP4 for a missense variant when the primary missense predictor (REVEL) is inconclusive rather than clearly benign. Because no calibrated in silico tool reaches a benign-supporting threshold, BP4 is not met.
generic_acmg_BP4_computational_supporting
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.883G>A in TARDBP is a missense substitution predicted to produce NP_031401.1:p.(Gly295Ser). 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 = 0.501. BayesDel score = 0.285256.
9 paper records listed. 4 cited in the classification.
We also identified two novel mutations (namely, p.G294V and p.G295S) in two sporadic ALS cases. The mutations are located within exon 6 in a highly conserved region of TDP-43 and were absent in 362 chromosomes from control individuals (Fig. 2).
Location Results, sequence-analysis paragraph; Table 2, patient E; Discussion, paragraph describing the two novel mutations
Context TARDBP coding-region sequencing in 314 ALS probands (308 Italian) compared to 181 healthy Italian volunteers (362 control chromosomes); exons 2-5 and first 528 nt of exon 6 amplified and directly sequenced.
With the exception of G295R, which has been identified in a single SALS individual, all other mutations have been found exclusively in FALS cases.
Location Table 1; Results, paragraph 2 (page 2097); Discussion, paragraph 2 (page 2098)
Context Exon 6 TARDBP mutational screening by touchdown PCR and Sanger sequencing in 376 AD patients, 463 PD patients, and 397 ALS patients (208 FALS, 188 SALS).
The p.Gly295Ser mutation was identified in an Italian patient (4; Table 1) who presented, at the age of 62, gait difficulties and, some months later, fell due to weakness and numbness in the left leg extremity.
Location Results, paragraph describing patient 4; Table 1
Context Screening of all coding exons and intron/exon boundaries of TARDBP in 61 Italian ALS patients using high-resolution melting analysis followed by sequencing.
Our study is the first to report the two TDP-43 C-terminus mutant peptides (G294V and G295S) displayed enhanced amyloidogenic and prion-like characteristics, which may contribute a toxic gain-of-function in TDP-43 proteinopathy.
Location Results, multiple subsections; Discussion
Context Synthetic TDP-43 C-terminal peptides (residues 287-322) evaluated by TEM, CD spectroscopy, ThT fluorescence, sedimentation/HPLC, liposome leakage assays, and N2a cell viability assays.
The p.D217N mutation in PDIA3 was observed in a sALS patient who also had a rare TARDBP variant (c.1017 G>C, p.G295R) previously described only in a single sALS case (Corrado et al., 2009; Lattante et al., 2013).
Results, section 3.1, paragraph 1
TDP-43G295R, TDP-43G295S, TDP-43M311V suppressed GFP mRNA expression, but not reaching statistical significant (Figure 6A). At the protein level, we found that TDP-43G295R, TDP-43G295S, and TDP-43M311V suppressed GFP expression significantly, while TDP-43A90V and TDP-43K263E promoted GFP expression (not statistically significant) (Figure 6B and C).
Results, subsection "ALS/FTLD-U-causing mutations of TDP-43 affect tau mRNA stability and tau expression differentially," Figure 6A-C
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
This variant is present in gnomAD v4.1 (AF= 1.23919e-06; MAF= 0.00012%, 2/1613954 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 1.6951e-06; MAF= 0.00017%, 2/1179872 alleles, homozygotes = 0); grpmax FAF= 2.8e-07.
This variant is present in gnomAD v2.1 (AF= 7.9628e-06; MAF= 0.00080%, 2/251168 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 1.76286e-05; MAF= 0.00176%, 2/113452 alleles, homozygotes = 0); grpmax FAF= 2.93e-06.
Absent from gnomAD-Canada v1.0.
This variant has been reported in ClinVar as Pathogenic (1 clinical laboratory). (ClinVarID = 21485)
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.501. BayesDel score = 0.285256.
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.