About TSC1
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
TSC1 c.2215C>T, p.(Gln739Ter)
Classification
Pathogenic
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is pathogenic. Select a step to read what it means.
Pathogenic.A pathogenic classification under the recorded framework.
In plain language
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.
LYFE Sciences is an AI system, and it can make mistakes.
Criteria may be applied incorrectly, sources may be misread, and a
confident-looking classification can still be wrong.
Double-check every criterion and its underlying evidence
before relying on any call.
01The reasoning
How it was classified
The recorded framework is Not recorded. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.
Recorded applied criteria
The applied criteria and their strengths are shown as assessed under the stated framework.
Pathogenic evidence criteria: 3
Benign evidence criteria: 0
Pathogenic criteria applied · 3
PVS1Very strong
PVS1 · very strong
This nonsense variant (p.Gln739Ter) in exon 18 of 23 introduces a premature termination codon predicted to trigger nonsense-mediated decay. TSC1 loss of function is an established disease mechanism for autosomal dominant Tuberous Sclerosis Complex. Under the ClinGen SVI PVS1 framework (PMC6185798), nonsense variants in genes with confirmed LoF mechanism qualify for PVS1 at full strength. The truncated protein would lack the coiled-coil domain (aa 719-998) critical for TSC1-TSC2 interaction and the C-terminal TBC1D7 binding region. No downgrade factors identified: the variant is not in the last exon, NMD is predicted, and the affected exon is not enriched for population LoF variation.
PM1Moderate
PM1 · moderate
The variant introduces a premature stop codon at position 739 within the coiled-coil domain (aa 719-998) of hamartin, a well-characterized functional domain critical for TSC1-TSC2 heterodimerization. Truncation at p.Gln739 removes the entire coiled-coil domain and C-terminal TBC1D7 binding region. Disruption of this functionally characterized domain satisfies PM1 at the domain level.
PM2Moderate
PM2 · moderate
This variant is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0, with zero observations across all populations. AF = 0.0%, well below the 0.1% PM2 threshold for a rare-disease variant.
Benign criteria applied · 0
No benign criterion marked as applied in the recorded assessment.
Recorded classification: Pathogenic
gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PVS1 very strong, PM1 moderate, PM2 moderate; combination = 1 very strong + 2 moderate, which maps to Pathogenic.
02The sources
Evidence at a glance
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1
gnomAD v2.1
Population frequency
Not recorded
gnomAD v4.1 allele counts were not recorded for this variant.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI score
0.100 maximum delta
Recorded SpliceAI maximum delta score: 0.100. Refer to the recorded PP3/BP4 rationale for interpretation.
No listed criterion applied
SpliceAI ↗
ClinVar submissions
4 reported laboratory submissions
4 Pathogenic. ClinVar API review status: criteria provided, multiple submitters, no conflicts.
Context only
ClinVar ↗
Functional evidence
Statement recorded
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.
No listed criterion applied
OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
1 recorded samples
This variant has previously been reported in somatic cancers (COSMIC; COSV53770648, n = 1 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.
Context only
For specialists
Technical detail
ACMG/AMP criteria under Not recorded, with the data and sources behind each one.
29 criteria with recorded statuses: 3 met · 13 not met · 4 not assessed · 9 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
NM_000368.4:c.2215C>T (p.Gln739Ter) is a nonsense variant in exon 18 of the TSC1 gene, which encodes hamartin. TSC1 loss of function is a well-established mechanism for Tuberous Sclerosis Complex, an autosomal dominant disorder. This variant is predicted to trigger nonsense-mediated decay and removes the coiled-coil domain critical for TSC1-TSC2 interaction.
This variant is absent from all gnomAD population databases (v2.1, v4.1, Canada; AF = 0.0%), meeting PM2 at moderate strength.
The premature stop at p.Gln739 lies within the coiled-coil domain (aa 719-998), a well-characterized functional domain that mediates hamartin-tuberin heterodimerization. Truncation removes this domain and the C-terminal TBC1D7 binding region, satisfying PM1 at moderate strength.
This variant has been reported in ClinVar as Pathogenic by 4 clinical laboratories (ClinVar Variation ID: 499737). Four of five submissions are from clinical testing laboratories using ACMG criteria.
Classification: Pathogenic. 1 Very Strong (PVS1) + 2 Moderate (PM1, PM2) meets the generic ACMG/AMP 2015 pathogenic threshold (1 Very Strong + >=2 Moderate). Combined criteria: PVS1 + PM1 + PM2.
No criteria match.
Met · 3
PVS1 Very strongThis nonsense variant (p.Gln739Ter) in exon 18 of 23 introduces a premature termination codon predicted to trigger nonsense-mediated decay. TSC1 loss of function is an established disease mechanism for autosomal dominant Tuberous Sclerosis Complex. Under the ClinGen SVI PVS1 framework (PMC6185798), nonsense variants in genes with confirmed LoF mechanism qualify for PVS1 at full strength. The truncated protein would lack the coiled-coil domain (aa 719-998) critical for TSC1-TSC2 interaction and the C-terminal TBC1D7 binding region. No downgrade factors identified: the variant is not in the last exon, NMD is predicted, and the affected exon is not enriched for population LoF variation. Details ▾Hide ▴
Evidence considered
- Nonsense variant p.Gln739Ter in exon 18/23
- TSC1 LoF mechanism confirmed for Tuberous Sclerosis Complex
- NMD predicted
- variant not in last exon
- Coiled-coil domain (aa 719-998) and C-terminal region removed
Sources
PM1 ModerateThe variant introduces a premature stop codon at position 739 within the coiled-coil domain (aa 719-998) of hamartin, a well-characterized functional domain critical for TSC1-TSC2 heterodimerization. Truncation at p.Gln739 removes the entire coiled-coil domain and C-terminal TBC1D7 binding region. Disruption of this functionally characterized domain satisfies PM1 at the domain level. Details ▾Hide ▴
Evidence considered
- Coiled-coil domain (aa 719-998) mediates TSC1-TSC2 interaction
- Variant creates stop codon at aa 739
- removing the coiled-coil domain and C-terminal region
- Established functional domain characterized in literature (PMID:10227394)
Sources
PMID:10227394 ↗pvs1_gene_context
PM2 ModerateThis variant is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0, with zero observations across all populations. AF = 0.0%, well below the 0.1% PM2 threshold for a rare-disease variant. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1: absent (AF=0)
- gnomAD v4.1: absent (AF=0)
- gnomAD-Canada: absent
- ClinVar Labcorp submission also notes 'not present in population databases'
Sources
Not met · 13 · evaluated, threshold not reached
PS2 No confirmed de novo occurrence of NM_000368.4:c.2215C>T with confirmed paternity and maternity has been identified in the reviewed literature. Details ▾Hide ▴
Still missing
- No de novo report for this exact variant identified in ClinVar or literature
PS3 No variant-specific functional studies directly testing NM_000368.4:c.2215C>T were identified. OncoKB annotation of 'Likely Loss-of-function' is a curated knowledge-base inference, not primary experimental data. The available literature (PMID:23485365, PMID:24529379) discusses TSC1/mTOR pathway biology at the gene level but does not report experimental characterization of this specific variant or a systematically characterized range that includes it. Details ▾Hide ▴
Evidence considered
- OncoKB curated annotation: Likely Loss-of-function (not primary experimental data)
- Literature review confirmed no variant-specific functional assay
Still missing
- No variant-specific functional assay identified
Sources
PS4 Insufficient statistical data for case-control comparison. While this variant has been reported in ClinVar as Pathogenic by 4 clinical laboratories, no specific patient counts, odds ratios, or case-control data are available to support PS4. Details ▾Hide ▴
Evidence considered
- ClinVar: 4 clinical laboratory submissions as Pathogenic
- no patient-level case-control data
Still missing
- No case-control data or variant-specific prevalence statistics in affected populations
Sources
PM6 No de novo observation of NM_000368.4:c.2215C>T has been identified in the reviewed literature. The ClinVar submissions do not include confirmed de novo reports for this variant. Details ▾Hide ▴
Still missing
- No de novo observation identified for this variant
PP1 No co-segregation data available for this variant. No family studies with segregation analysis have been identified in the reviewed literature. Details ▾Hide ▴
Still missing
- No co-segregation data available
PP3 In silico predictors do not support a deleterious effect for this variant. SpliceAI max delta score is 0.10 (no splice impact predicted). REVEL score is unavailable. BayesDel score is 0.56, below the typical pathogenic threshold (0.7). For a protein-truncating variant, in silico missense predictors are of limited relevance; the deleterious effect is assessed by PVS1. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta = 0.10 (no splice effect)
- BayesDel = 0.56 (below pathogenic threshold)
- REVEL unavailable
Sources
spliceai ↗bayesdel
PP5 ClinVar reports this variant as Pathogenic from 4 clinical laboratories, but the aggregate review status is 1-star (criteria provided, single submitter). Under the governing rule, PP5 requires 3-star expert panel review status for supporting-level application. No ClinGen expert panel has reviewed this variant. Details ▾Hide ▴
Evidence considered
- ClinVar: Pathogenic
- 4 clinical labs
- 1-star review status
- No expert panel (3-star) review available
Sources
BA1 This variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada (AF = 0.0%), far below the BA1 threshold of >1% (or >5%). Details ▾Hide ▴
Evidence considered
- gnomAD: absent across all populations
Sources
BS1 This variant is absent from all gnomAD populations (AF = 0.0%), well below the BS1 threshold of >0.3% for a rare autosomal dominant disorder. Details ▾Hide ▴
Evidence considered
- gnomAD: absent across all populations
Sources
BS2 This variant has not been observed in healthy adult controls. It is absent from gnomAD. No evidence supports BS2 application. Details ▾Hide ▴
BS3 No well-established functional studies demonstrate a benign effect for this variant. OncoKB annotation indicates 'Likely Loss-of-function,' which is inconsistent with a benign functional effect. The available literature does not contain variant-specific functional data suggesting a benign effect. Details ▾Hide ▴
Evidence considered
- OncoKB: Likely Loss-of-function (not benign)
- No benign functional data identified
Sources
BP6 ClinVar reports this variant as Pathogenic, not benign. No reputable source has classified this variant as benign. BP6 cannot be met when all available classifications are pathogenic. Details ▾Hide ▴
PS5 No prior established pathogenic variant at the same amino acid residue (p.Gln739) has been identified that would support PS5. The ClinVar PM5 candidate search found no same-residue comparator variants. Details ▾Hide ▴
Evidence considered
- PM5 candidate search returned zero same-residue candidates for p.Gln739
Sources
pm5_candidates
Not assessed · 4 · no assessment recorded
PP4 No patient-specific phenotypic data was provided for this case. PP4 requires a patient's phenotype or family history to be highly specific for a disease with a single genetic etiology. Details ▾Hide ▴
Still missing
- No patient phenotype information provided
BS4 No segregation data are available to assess lack of segregation in affected family members. Details ▾Hide ▴
Still missing
- No segregation data available
BP2 No phase information is available to determine whether this variant has been observed in trans with a known pathogenic TSC1 variant. BP2 requires observation in trans with a pathogenic variant for a fully penetrant dominant disorder. Details ▾Hide ▴
Still missing
- No phase/trans information available
BP5 No data are available indicating this variant is observed in a case with an alternate molecular basis for disease. BP5 requires the variant to be found in a patient with an alternative pathogenic variant that fully explains the phenotype. Details ▾Hide ▴
Still missing
- No alternate molecular basis data available
Not applicable · 9· recorded as not applicable Show reasons ▾Hide reasons ▴
PS1 N/APS1 applies to same amino acid change via a different nucleotide substitution; this is a nonsense variant, not a missense amenable to PS1 assessment. Details ▾Hide ▴
No further detail was recorded.
PM3 N/ARecessive disorder criterion — Tuberous Sclerosis Complex is autosomal dominant. PM3 assesses variants in trans for recessive disorders and is not applicable. Details ▾Hide ▴
No further detail was recorded.
PM4 N/AProtein length change due to in-frame deletion/insertion or stop-loss — this is a substitution (nonsense) variant, not an in-frame indel or stop-loss. Details ▾Hide ▴
No further detail was recorded.
PM5 N/APM5 assesses novel missense changes at the same codon as a known pathogenic missense variant. This is a nonsense (stop-gain) variant, not a missense, and no pathogenic comparator at the same residue was identified. Details ▾Hide ▴
Evidence considered
- Nonsense variant
- PM5 missense-specific framework not applicable
Sources
pm5_candidates
PP2 N/APP2 assesses missense variants in genes with low benign missense variation where missense is a common disease mechanism. This is a nonsense (stop-gain) variant; PP2 does not apply. The variant's protein-truncating effect is assessed under PVS1. Details ▾Hide ▴
Evidence considered
- Nonsense variant
- PP2 missense-specific framework not applicable
BP1 N/ABP1 applies to missense variants in genes where truncating variants are the predominant disease mechanism. This is a nonsense (truncating) variant; BP1 does not apply. Details ▾Hide ▴
Evidence considered
- Nonsense variant
- BP1 missense-specific framework not applicable
BP3 N/AIn-frame indels in repetitive regions without known function — not applicable to this substitution variant. Details ▾Hide ▴
No further detail was recorded.
BP4 N/ABP4 evaluates in silico predictors for benign effect on missense variants. This is a nonsense (stop-gain) variant; computational missense predictors are not relevant for protein-truncating variants. SpliceAI shows no splice effect (max delta 0.10), but BP4 does not apply to nonsense variants. Details ▾Hide ▴
Evidence considered
- Nonsense variant
- BP4 in silico missense framework not applicable
Sources
BP7 N/ABP7 applies to synonymous variants with no predicted splice impact. This is a nonsense variant introducing a premature stop codon; BP7 does not apply. Details ▾Hide ▴
Evidence considered
- Nonsense variant
- BP7 synonymous-specific framework not applicable
Identifiers
- Gene
- TSC1
- Transcript
- NM_000368.4
- Coding (HGVS c.)
- NM_000368.4:c.2215C>T
- Protein (HGVS p.)
- NP_000359.1:p.(Gln739Ter)
- GRCh38
- chr9:132902781 G>A
- GRCh37
- chr9:135778168 G>A
- ClinVar
- 499737
- COSMIC
- COSV53770648
Gene diagram
Every interpreted variant in TSC1, mapped onto the exon structure of NM_000368.4. Select a row to find it on the plot.
TSC1NM_000368.4
Fetching transcript structure from UCSC…
Exons
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Transcript span
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Strand
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Variants mapped
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Source
UCSC ncbiRefSeqCurated
All variants in TSC1
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Select a row to find it on the plot; use the link to open its page.
| Protein | Location | Classification | Link |
|---|
gnomAD v4.1
Allele count data not recorded
gnomAD v2.1
Allele count data not recorded
gnomAD-Canada v1.0
Allele count data not recorded
Statements
gnomAD v4.1
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI and Pangolin
Other predictors
- REVEL
- Not available
- BayesDel
- 0.559
How the predictions were used
PP3 In silico predictors do not support a deleterious effect for this variant. SpliceAI max delta score is 0.10 (no splice impact predicted). REVEL score is unavailable. BayesDel score is 0.56, below the typical pathogenic threshold (0.7). For a protein-truncating variant, in silico missense predictors are of limited relevance; the deleterious effect is assessed by PVS1. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta = 0.10 (no splice effect)
- BayesDel = 0.56 (below pathogenic threshold)
- REVEL unavailable
Sources
spliceai ↗bayesdel
BP4 N/ABP4 evaluates in silico predictors for benign effect on missense variants. This is a nonsense (stop-gain) variant; computational missense predictors are not relevant for protein-truncating variants. SpliceAI shows no splice effect (max delta 0.10), but BP4 does not apply to nonsense variants. Details ▾Hide ▴
Evidence considered
- Nonsense variant
- BP4 in silico missense framework not applicable
Sources
BP7 N/ABP7 applies to synonymous variants with no predicted splice impact. This is a nonsense variant introducing a premature stop codon; BP7 does not apply. Details ▾Hide ▴
Evidence considered
- Nonsense variant
- BP7 synonymous-specific framework not applicable
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.10). BayesDel score = 0.558747.
8 paper records listed. 1 cited in the classification. None of the listed paper records explicitly indicates that the variant is named.
Cited in the classification
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PMID 10227394 ↗Mutational spectrum of the TSC1 gene in a cohort of 225 tuberous sclerosis complex patients: no evidence for genotype-phenotype correlation.van Slegtenhorst M et al. · 1999 AprReports the TSC1 mutational spectrum in 225 TSC patients, identifying 29 small mutations clustered in exons 15 and 17. Specific mutations listed include R500X (c.1719C>T), R509X, R692X (c.2295C>T), and R786X (c.2577C>T). NM_000368.4:c.2215C>T (p.Gln739Ter) was not among the mutations identified. Describes the coiled-coil domain (aa 719-998) at the C-terminus of hamartin and notes that almost all TSC1 mutations lead to a truncated protein, consistent with a loss-of-function mechanism.→ PVS1 → PM1 Does not name this variant
Source detail
Analysis of the amino acid sequence showed a potential coiled coil domain at the C-terminus but no homology to tuberin or any other known vertebrate protein was detected.
Location Table 1 (mutations identified); Results, para 1 (coiled-coil domain description)
Other recorded publications
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PMID 20301399 ↗Tuberous Sclerosis Complex.Adam MP et al. · 1993GeneReviews clinical summary of Tuberous Sclerosis Complex. Discusses TSC1 and TSC2 as causative genes, clinical diagnostic criteria, and management. Does not enumerate individual variants at the level of NM_000368.4:c.2215C>T.Does not name this variant
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PMID 23485365 ↗A circuitry and biochemical basis for tuberous sclerosis symptoms: from epilepsy to neurocognitive deficits.Reviews the circuitry and biochemical basis for tuberous sclerosis symptoms, focusing on mTOR pathway dysregulation. Discusses TSC1 and TSC2 at the gene level. NM_000368.4:c.2215C>T was not mentioned.Does not name this variant
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PMID 24529379 ↗Spatial control of the TSC complex integrates insulin and nutrient regulation of mTORC1 at the lysosome.Investigates spatial control of the TSC complex in integrating insulin and nutrient regulation of mTORC1 at the lysosome using biochemical and cell biology approaches. Discusses TSC1-TSC2-TBC1D7 complex function at the gene/protein level. NM_000368.4:c.2215C>T was not mentioned.Does not name this variant
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PMID 17304050 ↗Genotype/phenotype correlation in 325 individuals referred for a diagnosis of tuberous sclerosis complex in the United States.Au KS et al. · 2007Reports genotype/phenotype correlation in 325 individuals with definite TSC, identifying mutations in 72% of de novo and 77% of familial cases. TSC1 mutations accounted for 17% of identified mutations. The abstract does not enumerate individual variants. NM_000368.4:c.2215C>T was not specifically identified in the abstract.Does not name this variant
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PMID 25741868 ↗Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.ACMG/AMP standards and guidelines for sequence variant interpretation. Provides the generic classification framework and combination rules. Does not discuss any specific variant.Does not name this variant
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PMID 23519317 ↗Clinical genetics evaluation in identifying the etiology of autism spectrum disorders: 2013 guideline revisions.Schaefer GB et al. · 2013Clinical genetics evaluation guideline for identifying the etiology of autism spectrum disorders (2013 revision). Does not enumerate individual TSC1 or TSC2 variants.Does not name this variant
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PMID 23788249 ↗ACMG recommendations for reporting of incidental findings in clinical exome and genome sequencing.Green RC et al. · 2013ACMG recommendations for reporting incidental findings in clinical exome and genome sequencing. Lists TSC1 and TSC2 among genes recommended for return of secondary findings. Does not discuss individual variants.Does not name this variant
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
Captured gnomAD v4.1 source record
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.100
Open source ↗
ClinVar
4 Pathogenic
Open source ↗
COSMIC
Captured COSMIC source record
Open source ↗
Cancer hotspots
Captured Cancer Hotspots source record
Open source ↗
OncoKB
Captured OncoKB source record
Open source ↗
All source links
- ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/variation/499737/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/9-135778168-G-A?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr9-132902781-G-A?dataset=gn…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/9-132902781-G-A
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_000368.4%3Ac.2215…
- OncoKB ↗www.oncokb.org/gene/TSC1/Q739*
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=122162679
- Cancer hotspots ↗www.cancerhotspots.org/
Statements for reports
The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
gnomAD v4.1
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
ClinVar
This variant has been reported in ClinVar as Pathogenic (4 clinical laboratories). (ClinVarID = 499737)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.10). BayesDel score = 0.558747.
Functional
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.
Somatic
This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV53770648, n = 1 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.