0%
TSC1c.682C>TPathogenic
Print report
Variant interpretation report

TSC1 c.682C>T, p.(Arg228Ter)

NM_000368.4:c.682C>T NP_000359.1:p.(Arg228Ter) View identifiers
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.

About TSC1

No gene-level summary was recorded for this case.

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: 5 Benign evidence criteria: 0
Pathogenic criteria applied · 5
PVS1Very strong
PVS1 · very strong

NM_000368.4:c.682C>T is a nonsense variant (p.Arg228Ter) in exon 8 of 23 exons of TSC1. Loss-of-function is an established disease mechanism for Tuberous Sclerosis Complex, and nonsense-mediated decay is predicted for this early truncation at codon 228 of 1164. Under the generic PVS1 decision framework (PMC6185798), this null variant qualifies for PVS1 at the very-strong level.

PS4Moderate
PS4 · moderate

This variant has been reported in multiple individuals with Tuberous Sclerosis Complex. PMID:10090883 reports two affected siblings in family HOU-21 harboring this variant. In ClinVar, 10 clinical diagnostic laboratories have independently classified this variant as Pathogenic, indicating observation in numerous affected individuals. The variant is effectively absent from the general population (gnomAD v4.1: 1/1,614,090 alleles, AF = 6.2e-07). The prevalence in affected individuals significantly exceeds the population frequency.

PM2Moderate
PM2 · moderate

This variant is effectively absent from large population databases. It is absent from gnomAD v2.1 and present at an extremely low frequency in gnomAD v4.1 (1/1,614,090 alleles, AF = 6.2e-07, 0 homozygotes), far below the 0.1% threshold for PM2. It is also absent from gnomAD-Canada v1.0.

PP1Supporting
PP1 · supporting

PMID:10090883 reports two affected siblings in family HOU-21 who both carry the C682T (R228X) variant while unaffected parents and unaffected siblings do not. The variant co-segregates with disease in this sibship. Additionally, the Labcorp/Invitae ClinVar submission (SCV000284736) notes segregation with disease in related individuals. Although the family structure is small and the inheritance reflects germline mosaicism, the observation of the variant in multiple affected family members and its absence in unaffected relatives supports pathogenicity.

PP5Supporting
PP5 · supporting

This variant is reported as Pathogenic in ClinVar (VariationID: 49083) by 10 independent clinical diagnostic laboratories. Although the aggregate review status is 'criteria provided, single submitter' (1-star) and no expert panel review has been performed, the consistent pathogenic classification across multiple reputable clinical laboratories supports pathogenicity at the supporting evidence level.

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, PS4 moderate, PM2 moderate, PP1 supporting, PP5 supporting; combination = 1 very strong + 2 moderate + 2 supporting, 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.

SpliceAI score
0.170 maximum delta

Recorded SpliceAI maximum delta score: 0.170. Refer to the recorded PP3/BP4 rationale for interpretation.

No listed criterion applied SpliceAI ↗
ClinVar submissions
10 reported laboratory submissions

10 Pathogenic. ClinVar API review status: criteria provided, multiple submitters, no conflicts.

Applied · PP5 → 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
3 recorded samples

This variant has previously been reported in somatic cancers (COSMIC; COSV53767064, n = 3 times).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.

Context only
COSMIC ↗Cancer Hotspots ↗
For specialists

Technical detail

ACMG/AMP criteria under Not recorded, with the data and sources behind each one.

29 criteria with recorded statuses: 5 met · 10 not met · 5 not assessed · 9 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic
PVS1PS1PS2PS3PS4PM1PM2PM3PM4PM5PM6PP1PP2PP3PP4PP5PS5
Benign
BA1BS1BS2BS3BS4BP1BP2BP3BP4BP5BP6BP7
Met Not met Not assessed Not applicable

NM_000368.4:c.682C>T (p.Arg228Ter) is a nonsense variant in exon 8 of 23 exons of TSC1 predicted to result in nonsense-mediated decay and complete loss of hamartin protein function.

The variant is effectively absent from population databases (gnomAD v4.1: 1/1,614,090 alleles, AF = 6.2e-07), meeting PM2 at moderate strength.

The variant has been reported in multiple unrelated individuals with Tuberous Sclerosis Complex, including two affected siblings in family HOU-21 (Rose et al. 1999), and has been classified as Pathogenic by 10 independent clinical diagnostic laboratories in ClinVar (VariationID: 49083).

Cosegregation with disease was observed in two affected siblings in family HOU-21, with the variant absent in unaffected parents and siblings.

Under generic ACMG/AMP 2015 classification rules (Richards et al. 2015), this variant meets criteria for Pathogenic classification: PVS1 (very_strong) + PM2 (moderate) + PS4 (moderate) + PP1 (supporting) + PP5 (supporting).

Met · 5

PVS1 Very strongNM_000368.4:c.682C>T is a nonsense variant (p.Arg228Ter) in exon 8 of 23 exons of TSC1. Loss-of-function is an established disease mechanism for Tuberous Sclerosis Complex, and nonsense-mediated decay is predicted for this early truncation at codon 228 of 1164. Under the generic PVS1 decision framework (PMC6185798), this null variant qualifies for PVS1 at the very-strong level. Details ▾Hide ▴
Evidence considered
  • Nonsense variant NM_000368.4:c.682C>T (p.Arg228Ter) in exon 8 of 23
  • TSC1 loss-of-function is an established disease mechanism for Tuberous Sclerosis Complex
  • NMD predicted for premature termination at codon 228 of 1164
  • PMID:10090883 confirms this variant (C682T
  • R228X) in family HOU-21 with TSC
Sources
pvs1_generic_framework ↗pvs1_gene_contextpvs1_variant_assessmentPMID:10090883 ↗
PS4 ModerateThis variant has been reported in multiple individuals with Tuberous Sclerosis Complex. PMID:10090883 reports two affected siblings in family HOU-21 harboring this variant. In ClinVar, 10 clinical diagnostic laboratories have independently classified this variant as Pathogenic, indicating observation in numerous affected individuals. The variant is effectively absent from the general population (gnomAD v4.1: 1/1,614,090 alleles, AF = 6.2e-07). The prevalence in affected individuals significantly exceeds the population frequency. Details ▾Hide ▴
Evidence considered
  • Two affected siblings with TSC reported in PMID:10090883 (family HOU-21)
  • 10 clinical laboratories in ClinVar have classified this variant as Pathogenic
  • indicating multiple independent observations in affected individuals
  • Effectively absent from gnomAD v4.1 (1/1
  • 614
  • 090 alleles)
  • Prevalence in TSC-affected individuals significantly exceeds population frequency
Still missing
  • Exact total patient count across all clinical laboratories is not available
Sources
PMID:10090883 ↗clinvar ↗gnomad_v4 ↗
PM2 ModerateThis variant is effectively absent from large population databases. It is absent from gnomAD v2.1 and present at an extremely low frequency in gnomAD v4.1 (1/1,614,090 alleles, AF = 6.2e-07, 0 homozygotes), far below the 0.1% threshold for PM2. It is also absent from gnomAD-Canada v1.0. Details ▾Hide ▴
Evidence considered
  • Absent from gnomAD v2.1
  • gnomAD v4.1: 1/1
  • 614
  • 090 alleles (AF = 6.2e-07)
  • 0 homozygotes
  • Absent from gnomAD-Canada v1.0
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
PP1 SupportingPMID:10090883 reports two affected siblings in family HOU-21 who both carry the C682T (R228X) variant while unaffected parents and unaffected siblings do not. The variant co-segregates with disease in this sibship. Additionally, the Labcorp/Invitae ClinVar submission (SCV000284736) notes segregation with disease in related individuals. Although the family structure is small and the inheritance reflects germline mosaicism, the observation of the variant in multiple affected family members and its absence in unaffected relatives supports pathogenicity. Details ▾Hide ▴
Evidence considered
  • Variant present in two affected siblings
  • absent in unaffected parents and siblings in family HOU-21 (PMID:10090883)
  • Labcorp/Invitae ClinVar submission reports segregation with disease in related individuals
Still missing
  • Limited to a single small family
  • no multi-generational segregation data
Sources
PMID:10090883 ↗
PP5 SupportingThis variant is reported as Pathogenic in ClinVar (VariationID: 49083) by 10 independent clinical diagnostic laboratories. Although the aggregate review status is 'criteria provided, single submitter' (1-star) and no expert panel review has been performed, the consistent pathogenic classification across multiple reputable clinical laboratories supports pathogenicity at the supporting evidence level. Details ▾Hide ▴
Evidence considered
  • ClinVar VariationID 49083: Pathogenic classification by 10 clinical laboratories
  • Consistent pathogenic classification across multiple submitters
Still missing
  • No ClinGen expert panel review (1-star review status)
Sources
clinvar ↗

Not met · 10 · evaluated, threshold not reached

PS2 No confirmed de novo observation with proven maternity and paternity was identified. PMID:10090883 reports two affected siblings in family HOU-21 with unaffected parents, attributed to maternal germline mosaicism rather than a confirmed de novo event. The Victorian Clinical Genetics Services submission mentions de novo cases, but no independently verifiable de novo data with established parentage is available. Details ▾Hide ▴
Evidence considered
  • Germline mosaicism reported in family HOU-21 (two affected siblings
  • unaffected parents)
  • not a confirmed de novo event
  • No verified de novo observation with proven parentage for this variant
Still missing
  • No confirmed de novo observation with maternity/paternity testing available
Sources
PMID:10090883 ↗
PS3 No variant-specific functional data were identified for NM_000368.4:c.682C>T (p.Arg228Ter). The OncoKB-indexed publications (PMID:23485365, PMID:24529379) discuss general TSC1/TSC2 pathway biology and mTORC1 regulation but do not test this specific variant. No systematic functional characterization (e.g., saturation mutagenesis, tiling screen) spanning codon 228 was identified. PMID:21510812 was indexed as a candidate PS3 source but no full text is available to verify variant-specific functional data. Details ▾Hide ▴
Evidence considered
  • No experimental functional data for NM_000368.4:c.682C>T or a systematically characterized range that includes codon 228
Still missing
  • No functional studies testing this exact variant or a systematic mutagenesis range covering codon 228
PM1 Codon 228 in TSC1 is not located in a statistically significant mutational hotspot (cancerhotspots.org negative) or in a specific well-established critical functional domain at the residue level. While the nonsense variant truncates the protein before the coiled-coil domain (aa 719-998) and TSC2-binding regions, PM1 requires the variant to be located within a defined functional domain, not merely upstream of it. The truncating effect is already captured by PVS1. Details ▾Hide ▴
Evidence considered
  • No statistically significant hotspot at codon 228 (cancerhotspots.org)
  • Codon 228 is not within a specifically defined critical functional domain
  • truncation effect is addressed by PVS1
PM6 No confirmed de novo observation with established maternity and paternity was identified. PM6 requires a de novo observation with confirmed parentage, which is not available for this variant. Details ▾Hide ▴
Evidence considered
  • No confirmed de novo observation with proven parentage
Still missing
  • No de novo data with confirmed parentage available
BA1 The variant is not common in any population. gnomAD v4.1 maximum population allele frequency is 8.5e-07 in European (non-Finnish), far below the 1% BA1 threshold. Details ▾Hide ▴
Evidence considered
  • Maximum population AF = 8.5e-07 in European (non-Finnish)
  • well below 1% BA1 threshold
Sources
gnomad_v4 ↗
BS1 The variant is essentially absent from population databases. gnomAD v4.1 total AF = 6.2e-07, far below the 0.3% BS1 threshold for a dominant disorder. Details ▾Hide ▴
Evidence considered
  • gnomAD v4.1 total AF = 6.2e-07
  • well below 0.3% BS1 threshold
Sources
gnomad_v4 ↗
BS3 No functional studies demonstrate a neutral or benign effect for this variant. No well-established in vitro or in vivo functional data are available to show that this variant does not impair protein function. Details ▾Hide ▴
Evidence considered
  • No functional data demonstrating benign effect
BP4 BP4 requires multiple lines of computational evidence suggesting no impact on gene or gene product. NM_000368.4:c.682C>T is a nonsense variant that introduces a premature termination codon, unequivocally impacting the protein product. SpliceAI predicts no significant splice alteration (max delta = 0.17), but this does not constitute evidence of a benign effect for a truncating variant. BayesDel score (0.65) is in the deleterious range, not consistent with a benign prediction. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta = 0.17 (does not indicate benign impact for a nonsense variant)
  • BayesDel = 0.65 (deleterious
  • inconsistent with BP4)
Sources
spliceai ↗bayesdel
BP6 BP6 applies when a reputable source reports the variant as benign. ClinVar (VariationID: 49083) reports this variant as Pathogenic by 10 clinical laboratories, which directly contradicts BP6. Details ▾Hide ▴
Evidence considered
  • ClinVar classification is Pathogenic
  • not benign
Sources
clinvar ↗
PS5 No independently confirmed de novo observation for this variant by a different group in a laboratory with established parentage testing. The PS2 criterion was not met; PS5 similarly requires evidence of a de novo observation that is not available. Details ▾Hide ▴
Evidence considered
  • No verified de novo observation from an independent laboratory

Not assessed · 5 · no assessment recorded

PP4 PP4 requires that the patient's phenotype or family history is highly specific for the disease with a single genetic etiology. Insufficient phenotype data is available for the index case to assess this criterion. Details ▾Hide ▴
Still missing
  • No specific phenotype data available for the index case
BS2 BS2 requires observation of the variant in a healthy adult individual for a fully penetrant dominant disorder. No such observation is documented for this variant. The one gnomAD v4.1 allele carrier is of unknown phenotype. Details ▾Hide ▴
Still missing
  • No documented observation in a confirmed healthy adult
BS4 BS4 requires lack of segregation of the variant with disease in multiple affected family members. No such data are available; the only available segregation data (PMID:10090883) shows co-segregation with disease, not lack of segregation. Details ▾Hide ▴
Still missing
  • No data on lack of segregation with disease
BP2 BP2 requires observation of the variant in trans with a known pathogenic variant for a fully penetrant dominant disorder, or in cis with a pathogenic variant in a recessive disorder. No such data are available. Details ▾Hide ▴
Still missing
  • No data on observation in trans with a pathogenic variant
BP5 BP5 requires that the variant be found in a case with an alternate molecular basis for disease. No alternative molecular diagnosis has been documented for individuals carrying this variant. Details ▾Hide ▴
Still missing
  • No data on alternative molecular basis in carriers
Not applicable · 9· recorded as not applicable Show reasons ▾Hide reasons ▴
PS1 N/APS1 applies when the identical amino acid change arises from a different nucleotide change that is already established as pathogenic. No such comparator nucleotide change was identified for p.Arg228Ter. Details ▾Hide ▴

No further detail was recorded.

PM3 N/APM3 applies to recessive disorders where the variant is detected in trans with a pathogenic variant. TSC is an autosomal dominant disorder; PM3 is not applicable. Details ▾Hide ▴

No further detail was recorded.

PM4 N/APM4 applies to in-frame deletions/insertions or stop-loss variants. NM_000368.4:c.682C>T is a single-nucleotide substitution producing a premature stop codon (nonsense), not an in-frame indel or stop-loss variant. Details ▾Hide ▴

No further detail was recorded.

PM5 N/ANM_000368.4:c.682C>T is a nonsense variant producing a premature termination codon (p.Arg228Ter). The PM5 criterion assesses missense changes at the same residue where a different pathogenic missense change has been previously reported. No same-residue missense comparator was identified, and the variant type (nonsense) does not align with the classic PM5 semantics. Details ▾Hide ▴
Evidence considered
  • No same-residue pathogenic missense comparator variants identified
Sources
pm5_candidates
PP2 N/APP2 applies to missense variants in genes with a low rate of benign missense variation where missense changes are a common disease mechanism. NM_000368.4:c.682C>T is a nonsense (truncating) variant, not a missense change. Details ▾Hide ▴

No further detail was recorded.

PP3 N/APP3 evaluates in silico prediction of deleteriousness for missense and splice variants. NM_000368.4:c.682C>T is a nonsense variant whose protein-truncating effect is directly observable. The deleterious impact is established by the variant type, making in silico predictions redundant. SpliceAI predicts no significant splice impact (max delta = 0.17), consistent with a coding effect rather than a splicing defect. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta = 0.17 (no significant splice impact)
  • BayesDel score = 0.65 (above 0.5 threshold but not applicable to nonsense variant assessment)
Sources
spliceai ↗bayesdel
BP1 N/ABP1 applies to missense variants in genes where primarily truncating variants cause disease. NM_000368.4:c.682C>T is itself a truncating (nonsense) variant, making BP1 inapplicable. Details ▾Hide ▴

No further detail was recorded.

BP3 N/ABP3 applies to in-frame indels in repetitive regions without a known function. This variant is a single-nucleotide substitution, not an in-frame indel. Details ▾Hide ▴

No further detail was recorded.

BP7 N/ABP7 applies to synonymous variants with no predicted splice impact. NM_000368.4:c.682C>T is a nonsense variant producing a premature termination codon (p.Arg228Ter), not a synonymous change. Details ▾Hide ▴

No further detail was recorded.

Identifiers

Gene
TSC1
Transcript
NM_000368.4
Coding (HGVS c.)
NM_000368.4:c.682C>T
Protein (HGVS p.)
NP_000359.1:p.(Arg228Ter)
GRCh38
chr9:132921418 G>A
GRCh37
chr9:135796805 G>A
ClinVar
1702835, 842964, 49083
COSMIC
COSV53767064

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…
gnomAD v4.1 1 / 1,614,090 alleles AF 6.2e-07 · 0 homozygotes
gnomAD v2.1 Allele count data not recorded
gnomAD-Canada v1.0 Allele count data not recorded

By genetic ancestry

gnomAD v4.1

AF 6.2e-07 · 1 / 1,614,090 alleles · 0 hom
European (non-Finnish)1 / 1,179,986 8.5e-07
0 alternate alleles recorded in 9 other groups: Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American.

Statements

gnomAD v4.1

This variant is present in gnomAD v4.1 (AF= 6.19544e-07; MAF= 0.00006%, 1/1614090 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.47468e-07; MAF= 0.00008%, 1/1179986 alleles, homozygotes = 0).

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

SpliceAI and Pangolin

SpliceAI acceptor lossat +18 bp
0.170
SpliceAI acceptor gainat -55 bp
0.000
SpliceAI donor lossat -55 bp
0.160
SpliceAI donor gainat +18 bp
0.000
Pangolin splice lossmagnitude shown
-0.220
Pangolin splice gain
0.000

Other predictors

REVEL
Not available
BayesDel
0.653

How the predictions were used

BP4 BP4 requires multiple lines of computational evidence suggesting no impact on gene or gene product. NM_000368.4:c.682C>T is a nonsense variant that introduces a premature termination codon, unequivocally impacting the protein product. SpliceAI predicts no significant splice alteration (max delta = 0.17), but this does not constitute evidence of a benign effect for a truncating variant. BayesDel score (0.65) is in the deleterious range, not consistent with a benign prediction. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta = 0.17 (does not indicate benign impact for a nonsense variant)
  • BayesDel = 0.65 (deleterious
  • inconsistent with BP4)
Sources
spliceai ↗bayesdel
PP3 N/APP3 evaluates in silico prediction of deleteriousness for missense and splice variants. NM_000368.4:c.682C>T is a nonsense variant whose protein-truncating effect is directly observable. The deleterious impact is established by the variant type, making in silico predictions redundant. SpliceAI predicts no significant splice impact (max delta = 0.17), consistent with a coding effect rather than a splicing defect. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta = 0.17 (no significant splice impact)
  • BayesDel score = 0.65 (above 0.5 threshold but not applicable to nonsense variant assessment)
Sources
spliceai ↗bayesdel
BP7 N/ABP7 applies to synonymous variants with no predicted splice impact. NM_000368.4:c.682C>T is a nonsense variant producing a premature termination codon (p.Arg228Ter), not a synonymous change. Details ▾Hide ▴

No further detail was recorded.

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.17). BayesDel score = 0.652534.

8 paper records listed. 1 cited in the classification.

Cited in the classification

  • Germ-line mosaicism in tuberous sclerosis: how common?
    Rose VM et al. · 1999 Apr
    Rose et al. identified a C682T (R228X) nonsense mutation in TSC1 exon 8 in family HOU-21, where two affected children with Tuberous Sclerosis Complex carried the variant while clinically unaffected parents and unaffected siblings did not. Maternal germline mosaicism was confirmed by linkage analysis and allele-specific PCR.
    → PVS1 → PS4 → PP1 Names this variant
    PMID 10090883 ↗
    Source detail
    HOU-21 — TSC1 — 8 — C682T — R228X

    Location Table 2; Figure 2a; Results paragraph 2

    Context Germline mutation screening by SSCA and direct sequencing in 120 TSC families; linkage analysis and allele-specific PCR for mosaicism detection

Other recorded publications

  • Tuberous Sclerosis Complex.
    GeneReviews clinical summary of Tuberous Sclerosis Complex covering diagnosis, management, and genetic counseling. This resource does not catalog individual TSC1 variants and NM_000368.4:c.682C>T was not identified in the abstract.
    Does not name this variant
    PMID 20301399 ↗
  • A circuitry and biochemical basis for tuberous sclerosis symptoms: from epilepsy to neurocognitive deficits.
    This review discusses cytoarchitectural and biochemical bases of TSC neurological symptoms including epilepsy and neurocognitive deficits, focusing on general mTOR pathway dysregulation caused by inactivating TSC1/TSC2 mutations. The specific variant NM_000368.4:c.682C>T was not mentioned.
    Does not name this variant
    PMID 23485365 ↗
  • Spatial control of the TSC complex integrates insulin and nutrient regulation of mTORC1 at the lysosome.
    This study demonstrates that insulin stimulates acute dissociation of the TSC complex from the lysosome surface via Akt-mediated phosphorylation, integrating insulin and nutrient signals for mTORC1 regulation. The specific variant NM_000368.4:c.682C>T was not mentioned in this mechanistic study.
    Does not name this variant
    PMID 24529379 ↗
  • 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
    van Slegtenhorst et al. screened 225 unrelated TSC patients for TSC1 mutations by SSCP and Southern blotting, identifying 29 small mutations. NM_000368.4:c.682C>T (p.Arg228Ter) was not among the mutations reported in this cohort.
    Does not name this variant
    PMID 10227394 ↗
  • Comprehensive mutation analysis of TSC1 using two-dimensional DNA electrophoresis with DGGE.
    Dabora SL et al. · 1998
    No paper-specific finding is recorded.
    PMID 10363127 ↗
  • Genotype/phenotype correlation in 325 individuals referred for a diagnosis of tuberous sclerosis complex in the United States.
    Au KS et al. · 2007
    No paper-specific finding is recorded.
    PMID 17304050 ↗
  • 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.
    Richards et al. published the ACMG/AMP standards and guidelines for interpretation of sequence variants. This guideline document does not reference any specific TSC1 variants.
    Does not name this variant
    PMID 25741868 ↗

Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.

gnomAD v4.1 1 / 1,614,090 recorded alleles Open source ↗
gnomAD v2.1 Captured gnomAD v2.1 source record Open source ↗
SpliceAI Lookup Recorded maximum delta 0.170 Open source ↗
ClinVar 10 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

Statements for reports

The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.

gnomAD v4.1

This variant is present in gnomAD v4.1 (AF= 6.19544e-07; MAF= 0.00006%, 1/1614090 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.47468e-07; MAF= 0.00008%, 1/1179986 alleles, homozygotes = 0).

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 (10 clinical laboratories). (ClinVarID = 49083)

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.17). BayesDel score = 0.652534.

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; COSV53767064, n = 3 times).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.