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.1 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.2 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).3 Cosegregation with disease was observed in two affected siblings in family HOU-21, with the variant absent in unaffected parents and siblings.4 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).5
TSC1
Final classification
Pathogenic
TSC1 c.682C>T · p.Arg228Ter
TSC1
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.
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.
Classification rationale
PVS1PS4PM2PP1PP5
Pathogenic
TSC1 c.682C>T
PVS1 + PS4 + PM2 + PP1 + PP5
→
Pathogenic
1
pvs1_generic_framework ↗pvs1_gene_contextPMID:10090883 ↗
5
generic_acmg_combination_rules
Gene diagram
· NM_000368.4 · variants mapped to exon structure
TSC1
NM_000368.4
Fetching transcript structure from UCSC…
Applied criteria · 5 applied · 14 assessed
Applied · 5
Strength
Supporting
Moderate
Strong
Very strong
✓
PVS1
very strong
Pathogenic
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.
Nonsense variant NM_000368.4:c.682C>T (p.Arg228Ter) in exon 8 of 23TSC1 loss-of-function is an established disease mechanism for Tuberous Sclerosis ComplexNMD predicted for premature termination at codon 228 of 1164
✓
PS4
moderate
Pathogenic
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.
Two affected siblings with TSC reported in PMID:10090883 (family HOU-21)10 clinical laboratories in ClinVar have classified this variant as Pathogenicindicating multiple independent observations in affected individuals
✓
PM2
moderate
Pathogenic
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.
Absent from gnomAD v2.1gnomAD v4.1: 1/1614
✓
PP1
supporting
Pathogenic
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.
Variant present in two affected siblingsabsent in unaffected parents and siblings in family HOU-21 (PMID:10090883)Labcorp/Invitae ClinVar submission reports segregation with disease in related individuals
✓
PP5
supporting
Pathogenic
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.
ClinVar VariationID 49083: Pathogenic classification by 10 clinical laboratoriesConsistent pathogenic classification across multiple submitters
Assessed · not applied
Pathogenic
PS2
No confirmed de novo observation with proven maternity and paternity was identified.
PS3
No variant-specific functional data were identified for NM_000368.4:c.682C>T (p.Arg228Ter).
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.
PM6
No confirmed de novo observation with established maternity and paternity was identified.
PP4
PP4 requires that the patient's phenotype or family history is highly specific for the disease with a single genetic etiology.
Benign
BA1
The variant is not common in any population.
BS1
The variant is essentially absent from population databases.
BS2
BS2 requires observation of the variant in a healthy adult individual for a fully penetrant dominant disorder.
BS3
No functional studies demonstrate a neutral or benign effect for this variant.
BS4
BS4 requires lack of segregation of the variant with disease in multiple affected family members.
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.
BP4
BP4 requires multiple lines of computational evidence suggesting no impact on gene or gene product.
BP5
BP5 requires that the variant be found in a case with an alternate molecular basis for disease.
BP6
BP6 applies when a reputable source reports the variant as benign.
N/A · 9
PS1 · PM3 · PM4 · PM5 · PP2 · PP3 · BP1 · BP3 · BP7
Research & evidence
Population frequency · supports pathogenic
gnomAD v4.1
gnomAD v2.1
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).
v2.1
Absent from gnomAD v2.1.
🇨🇦 CA
Absent from gnomAD-Canada v1.0.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
6.2e-05%
· 1 / 1,614,090
0 hom
0 hom
European (non-Finnish) 1 / 1,179,986 |
8.5e-05% |
+ 9 not observed (Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American)
gnomAD v2.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
gnomAD Canada 🇨🇦
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
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
Likely Oncogenic
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.
COSMIC
Cancer hotspots
Somatic evidence
Not in COSMIC / hotspots
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV53767064, n = 3 times).
Hotspots
This variant does not lie in a statistically significant hotspot.
Literature · how each cited paper was used
1papers cited
Each card is an audit: what was searched, what was found, whether it names the variant, which criteria it fed, and why. 7 further PMIDs triaged but not cited — see Sources & References.
Germ-line mosaicism in tuberous sclerosis: how common?
Searched
c.682C>TC682Tp.Arg228TerR228X
Found
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.
Variant
✓ Names this variant — characterised directly
Applied to
→PP1 supports · met
→PS4 supports · met
→PVS1 supports · met
Why
Variant directly observed in two affected siblings with TSC. Referenced for PVS1 (confirms nonsense variant in TSC patients), PS4 (multiple affected individuals), and PP1 (cosegregation with disease).
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 · full text
Sources & reference links
Triaged references · 7 PMIDs not cited in assessment
23485365 ↗
A circuitry and biochemical basis for tuberous sclerosis symptoms: from epilepsy to neurocognitive deficits.
ONCOKB
24529379 ↗
Spatial control of the TSC complex integrates insulin and nutrient regulation of mTORC1 at the lysosome.
ONCOKB
10227394 ↗
Mutational spectrum of the TSC1 gene in a cohort of 225 tuberous sclerosis complex patients: no evidence for genotype-phenotype correlation.
CLINVAR
10363127 ↗
Comprehensive mutation analysis of TSC1 using two-dimensional DNA electrophoresis with DGGE.
CLINVAR
17304050 ↗
Genotype/phenotype correlation in 325 individuals referred for a diagnosis of tuberous sclerosis complex in the United States.
CLINVAR
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.
CLINVAR