NM_000368.4:c.1801C>A

TSC1 · NP_000359.1:p.(Pro601Thr) · NM_000368.4

GRCh37: chr9:135781164 G>T · GRCh38: chr9:132905777 G>T

Gene: TSC1 Transcript: NM_000368.4

Final call

VUS

PM2 supporting BP4 supporting benign

Variant details

Gene

TSC1

Transcript

NM_000368.4

Protein

NP_000359.1:p.(Pro601Thr)

gnomAD AF

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

NM_000368.4:c.1801C>A (p.Pro601Thr) is a missense variant in exon 15 of TSC1, which encodes a scaffold protein in the mTOR pathway; loss-of-function variants in TSC1 cause tuberous sclerosis complex (autosomal dominant).

This variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada population databases (PM2).

Multiple in silico tools predict no damaging effect: BayesDel score -0.201 (benign), SpliceAI max delta 0.02 (no splice impact), and REVEL score 0.453 (indeterminate, below pathogenic thresholds), meeting BP4 at supporting level.

ClinVar classifies this variant as Uncertain Significance (criteria provided, single submitter, 2 clinical laboratories); no expert panel classification is available.

No variant-specific functional studies, segregation data, case-control evidence, de novo observations, or same-residue pathogenic comparators were identified.

Overall, PM2 (supporting) and BP4 (supporting benign) are the only applicable criteria. These two opposing supporting-level criteria offset each other, resulting in a classification of Uncertain Significance per ACMG/AMP 2015 combination rules.

Final determination: Generic ACMG/AMP 2015 fallback rules do not meet benign, likely benign, likely pathogenic, or pathogenic combination thresholds, so the variant is classified as Variant of Uncertain Significance.

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	N/A	Missense variant (p.Pro601Thr) in exon 15; does not fulfill default null-variant criteria (nonsense, frameshift, or canonical ±1,2 splice sites). Per ClinGen SVI PVS1 framework (PMC6185798), generic PVS1 does not apply to missense variants.	pvs1_generic_framework
PS1	Not assessed	No known pathogenic missense variant at the same amino acid residue (Pro601) with a different amino acid change was identified. Pm5_candidates analysis found no same-residue pathogenic comparators, precluding application of PS1.
PS2	Not met	No de novo observation has been reported for this variant in the available evidence; no parentage-confirmed de novo data identified in ClinVar, literature, or databases.
PS3	Not met	No variant-specific functional studies have been reported. OncoKB classifies this variant as Unknown Oncogenic Effect with no variant-level functional evidence curated. No functional data identified in literature or databases.	oncokb
PS4	Not met	Variant is absent from gnomAD but no case-control or statistical enrichment evidence in affected individuals has been reported. No published cohort data demonstrating significant enrichment in cases versus controls for this variant.
PS5	N/A	TSC1-associated tuberous sclerosis complex is an autosomal dominant disorder. PS5 applies to recessive disorders where a pathogenic variant is found in trans.
PM1	Not met	Variant does not lie in a statistically significant mutational hotspot; hotspot analysis negative. Pro601 is not within an established functional domain where pathogenic missense variants cluster preferentially.
PM2	Met	This variant is absent from gnomAD v2.1 (exomes), gnomAD v4.1 (exomes/genomes), and gnomAD-Canada v1.0 (genomes), meeting the PM2 criterion for a rare variant with population frequency below 0.1%.	gnomad_v2 gnomad_v4 gnomad_canada
PM5	N/A	No same-residue pathogenic missense comparator identified. PM5 candidates analysis found no eligible pathogenic or likely pathogenic variants at Pro601 with a different amino acid change.
PM6	Not met	No de novo observation has been reported for this variant. No confirmed de novo occurrence with maternity/paternity confirmation available in ClinVar or literature.
PP1	Not met	No segregation data have been reported for this variant. No family studies demonstrating cosegregation with disease are available.
PP2	Not met	PP2 is applied when a gene has a low rate of benign missense variation and missense variants are a common disease mechanism. TSC1 has diverse pathogenic variant types (truncating, missense, splice); there is insufficient evidence to establish that TSC1 meets the PP2 gene-level threshold for this specific variant.
PP3	Not met	In silico predictions do not support a deleterious effect: REVEL score 0.453 (below 0.5 threshold for pathogenic prediction), BayesDel score -0.201 (benign prediction), SpliceAI max delta 0.02 (no predicted splice impact). Multiple lines of computational evidence do not converge on a damaging prediction.	revel bayesdel spliceai
PP4	Not met	No patient phenotype data are available for this specific variant. No clinical case descriptions with detailed phenotype have been published.
PP5	Not met	ClinVar classification is Uncertain Significance (criteria provided, single submitter, 2 clinical laboratories). This does not constitute a reputable source reporting the variant as pathogenic. No expert panel or professional society has classified this variant as pathogenic.	clinvar
BA1	Not met	Variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada. Allele frequency is 0%, far below the 1% BA1 threshold.	gnomad_v2 gnomad_v4 gnomad_canada
BS1	Not met	Variant is absent from gnomAD. Allele frequency is 0%, below the 0.3% BS1 threshold. Absence from population databases does not satisfy BS1.	gnomad_v2 gnomad_v4 gnomad_canada
BS2	Not met	Variant is absent from gnomAD; no evidence of observation in healthy adults. BS2 requires observation of the variant in a healthy adult individual for a fully penetrant dominant disorder; absence from population databases precludes its application.
BS3	Not met	No functional studies have been reported demonstrating a neutral or benign effect for this variant. OncoKB classification is Unknown Oncogenic Effect and does not constitute evidence of no deleterious impact.	oncokb
BS4	Not met	No segregation data demonstrating non-segregation with disease are available. No family studies have been reported for this variant.
BP1	Not met	BP1 applies to missense variants in genes where only truncating variants cause disease. TSC1 has both missense and truncating pathogenic variants associated with tuberous sclerosis complex; therefore BP1 is not applicable to TSC1 missense variants.
BP2	Not met	No evidence of observation in trans with a known pathogenic variant for this fully penetrant autosomal dominant disorder.
BP4	Met	Multiple lines of in silico evidence predict no damaging effect: BayesDel score -0.201 (benign prediction), SpliceAI max delta 0.02 (no predicted splice impact), and REVEL score 0.453 (indeterminate, below standard pathogenic thresholds). The convergence of benign and neutral computational predictions meets BP4 at supporting level.	revel bayesdel spliceai
BP5	Not met	No evidence that an alternative molecular basis explains disease in any case where this variant was observed. No case-level data available to evaluate BP5.
BP6	Not met	ClinVar classification is Uncertain Significance, not Benign or Likely Benign. BP6 requires a reputable source to classify the variant as benign/likely benign, which has not occurred.	clinvar
BP7	N/A	Missense variant (c.1801C>A, p.Pro601Thr). BP7 applies only to synonymous or non-coding variants with no predicted splice impact; this is a non-synonymous amino acid substitution.

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