Classification rationale

PVS1PM2 Likely Pathogenic

TSC1 c.163C>T nonsense · exon 4

PVS1 (Very Strong): nonsense variant p.(Gln55Ter) in exon 4 of 23 is predicted to trigger nonsense-mediated decay, removing about 95% of the 1164-amino-acid protein; germline loss-of-function is an established TSC1 disease mechanism. PM2 (Moderate): the variant is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0. Synthesis: PVS1 (Very Strong) + PM2 (Moderate) maps to Likely Pathogenic under the generic ACMG/AMP 2015 combination rules.

PVS1 + PM2 → Likely Pathogenic

Gene diagram · NM_000368.5 · variants mapped to exon structure

TSC1 NM_000368.5

Fetching transcript structure from UCSC…

Applied criteria · 2 applied · 15 assessed

MetEvidence satisfies this criterion.

Not metEvaluated against available evidence; threshold not reached.

Not assessedApplies in principle, but no evidence was found to evaluate it.

N/ADoesn't apply to this variant type.

Applied · 2

Strength Supporting Moderate Strong Very strong

✓

PVS1 very strong Pathogenic

Met (Very Strong): nonsense change p.(Gln55Ter) in exon 4 of 23 is predicted to trigger nonsense-mediated decay, removing about 95% of the protein.

pvs1_variant_assessment.json: transcript_hgvs NM_000368.5:c.163C>T, protein_1l NP_000359.1:p.(Q55*), consequence_class 'nonsense', variant_bucket 'nonsense', framework_source PMC6185798, suggested_default_strength 'PVS1'.VariantValidator predicted protein alignment: position_first 54, position_last_predicted 55, position_last_original 1165 (i.e. wild-type protein length 1164 aa), confirming the truncation eliminates the vast majority of the protein.VariantValidator exonic position mapping places c.163C>T within exon 4 (start_exon/end_exon = '4') for both GRCh37 and GRCh38 coordinates.

pvs1_generic_framework ↗PMID:10227394 ↗

✓

PM2 moderate Pathogenic

Met (Moderate): the variant is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0.

No TSC1-specific ClinGen VCEP specification or local gene-specific framework was retrieved; generic ACMG/AMP assessment was used.The normalized exact variant is NC_000009.11:g.135802635G>A (GRCh37) / NC_000009.12:g.132927248G>A (GRCh38), corresponding to NM_000368.5:c.163C>T, p.(Gln55Ter).The variant was reported absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0, with no overall or ancestry-specific allele count or frequency reported.

gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

Assessed · not applied · 2 not met · 13 not assessed

Pathogenic

PS2 Not assessed: no documented de novo occurrence with both parents tested and biological parentage confirmed.

PS3 Not assessed: no validated functional assay data testing this exact variant was available.

PS4 Not assessed: no case-control or enrichment dataset for this exact variant was available.

PM6 Not assessed: the de novo claim lacks parental test results, phenotype, and parentage documentation.

PP1 Not assessed: no family segregation or pedigree data was available for this variant.

PP4 Not assessed: no proband phenotype documenting features specific to a TSC1-related disorder was provided.

PP5 Not assessed: ClinVar contains laboratory pathogenic submissions but no expert-panel assertion for this variant.

Benign

BA1 Not met: the variant is absent from population databases, so no allele frequency approaches the stand-alone benign threshold.

BS1 Not met: absent from all three population datasets, so no allele frequency exceeds the expected benign threshold.

BS2 Not assessed: no observation of the variant in a healthy adult, including no homozygote, was available.

BS3 Not assessed: no functional assay showing normal protein function for this exact variant was available.

BS4 Not assessed: no non-segregation observation, such as an affected relative lacking the variant, was available.

BP2 Not assessed: no phase data with a second pathogenic variant was available.

BP5 Not assessed: no alternative molecular diagnosis explaining the phenotype was provided.

BP6 Not assessed: no ClinVar expert-panel benign assertion exists for this variant.

N/A · 11 PS1 · PM1 · PM3 · PM4 · PM5 · PP2 · PP3 · BP1 · BP3 · BP4 · BP7

Research & evidence

Population frequency · supports pathogenic

gnomAD v4.1

gnomAD v2.1

v4.1

Absent from gnomAD v4.1.

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

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v2.1

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD Canada 🇨🇦

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v4 ↗ gnomAD v2 ↗ gnomAD 🇨🇦 ↗

ClinVar

This variant has been reported in ClinVar as Pathogenic (2 clinical laboratories). (ClinVarID = 48808)

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). BayesDel score = 0.60222.

SpliceAI ↗

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.

OncoKB ↗

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; COSV53765244, n = 5 times).

Hotspots

This variant does not lie in a statistically significant hotspot.

COSMIC ↗ Hotspots ↗

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.

Rule & framework references · cited for criterion definitions, not variant evidence

10227394 ↗ Mutational spectrum of the TSC1 gene in a cohort of 225 tuberous sclerosis complex patients: no evidence for genotype-phenotype correlation.

Sources & reference links

8Sources

ClinVar

gnomAD v2.1

gnomAD v4.1

gnomAD-Canada

SpliceAI

OncoKB

COSMIC

Cancer hotspots

Triaged references · 7 PMIDs not cited in assessment

20301399 ↗ Tuberous Sclerosis Complex. ONCOKB

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

12773163 ↗ Tuberous sclerosis complex (TSC) gene involvement in sporadic tumours. CLINVAR

17304050 ↗ Genotype/phenotype correlation in 325 individuals referred for a diagnosis of tuberous sclerosis complex in the United States. CLINVAR

22923433 ↗ Genome sequencing identifies a basis for everolimus sensitivity. CLINVAR

23401075 ↗ TSC1 involvement in bladder cancer: diverse effects and therapeutic implications. CLINVAR