PS1
Not assessed: no differently-coded variant producing the same p.Leu826Met substitution with an established pathogenic classification was identified.
PS2
Not assessed: no evidence that the variant arose de novo in an affected proband with confirmed maternity and paternity was available.
PS3
Not met: direct functional assays showed p.Leu826Met behaved like wild-type tuberin, with no damaging effect across any readout.
PS4
Not assessed: no case-control or enrichment evidence for this variant among individuals with tuberous sclerosis was available.
PM1
Not met: residue 826 lies in a broad ~900-residue N-terminal region rather than a small curated hotspot, and direct functional data show the substitution is nonpathogenic.
PM2
Not met: gnomAD v4.1 overall allele frequency is 0.135%, above the <0.1% PM2 rare-variant cutoff.
PM5
Not assessed: no same-residue missense change with an established pathogenic classification was identified; the only alternate, p.Leu826Pro, comes from a somatic functional panel.
PM6
Not assessed: no evidence of presumed de novo occurrence without confirmed parentage was available.
PP1
Not assessed: no supportive segregation series exists; the variant was inherited from an unaffected father, which is non-segregating.
PP2
Not assessed: no TSC2 missense constraint metric, such as a gnomAD missense Z-score, was available to evaluate this criterion.
PP3
Not met: REVEL score 0.638 is below the ≥0.644 PP3 supporting threshold, in the inconclusive zone.
PP4
Not assessed: no phenotype-specificity information for the tested individual was provided.
PP5
Not met: ClinVar has no expert-panel Pathogenic or Likely Pathogenic assertion for this exact variant.
