NM_000368.4:c.2215C>T

TSC1 · NP_000359.1:p.(Gln739Ter) · NM_000368.4

GRCh37: chr9:135778168 G>A · GRCh38: chr9:132902781 G>A

Gene: TSC1 Transcript: NM_000368.4

Final call

Pathogenic

PVS1 very strong PM1 moderate PM2 moderate

Variant details

Gene

TSC1

Transcript

NM_000368.4

Protein

NP_000359.1:p.(Gln739Ter)

gnomAD AF

ClinVar

Pathogenic

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

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.

Final determination: Generic ACMG/AMP 2015 fallback rules support a Pathogenic classification based on the observed combination of very strong, strong, moderate, and supporting pathogenic criteria.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PVS1	Met	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.	pvs1_generic_framework pvs1_gene_context pvs1_variant_assessment PMID:10227394
PS1	N/A	PS1 applies to same amino acid change via a different nucleotide substitution; this is a nonsense variant, not a missense amenable to PS1 assessment.
PS2	Not met	No confirmed de novo occurrence of NM_000368.4:c.2215C>T with confirmed paternity and maternity has been identified in the reviewed literature.
PS3	Not met	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.	oncokb PMID:23485365 PMID:24529379
PS4	Not met	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.	clinvar
PS5	Not met	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.	pm5_candidates
PM1	Met	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.	PMID:10227394 pvs1_gene_context
PM2	Met	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.	gnomad_v2 gnomad_v4 gnomad_canada clinvar
PM5	N/A	PM5 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.	pm5_candidates
PM6	Not met	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.
PP1	Not met	No co-segregation data available for this variant. No family studies with segregation analysis have been identified in the reviewed literature.
PP2	N/A	PP2 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.
PP3	Not met	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.	spliceai bayesdel
PP4	Not assessed	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.
PP5	Not met	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.	clinvar
BA1	Not met	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%).	gnomad_v2 gnomad_v4 gnomad_canada
BS1	Not met	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.	gnomad_v2 gnomad_v4 gnomad_canada
BS2	Not met	This variant has not been observed in healthy adult controls. It is absent from gnomAD. No evidence supports BS2 application.	gnomad_v2 gnomad_v4
BS3	Not met	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.	oncokb
BS4	Not assessed	No segregation data are available to assess lack of segregation in affected family members.
BP1	N/A	BP1 applies to missense variants in genes where truncating variants are the predominant disease mechanism. This is a nonsense (truncating) variant; BP1 does not apply.
BP2	Not assessed	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.
BP3	N/A	In-frame indels in repetitive regions without known function — not applicable to this substitution variant.
PM3	N/A	Recessive disorder criterion — Tuberous Sclerosis Complex is autosomal dominant. PM3 assesses variants in trans for recessive disorders and is not applicable.
PM4	N/A	Protein 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.
BP4	N/A	BP4 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.	spliceai
BP5	Not assessed	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.
BP6	Not met	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.	clinvar
BP7	N/A	BP7 applies to synonymous variants with no predicted splice impact. This is a nonsense variant introducing a premature stop codon; BP7 does not apply.

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