PS1
Not met: ClinVar has no pathogenic submissions for this amino acid change; 13 labs call it Benign or Likely benign, none P/LP.
PS2
Not assessed: no proband phenotype or de novo testing data were available.
PS3
Not assessed: no functional assay data for this variant were available; the reviewed SDHB functional study did not test p.Gly53Glu.
PS4
Not assessed: no exact-variant affected-case count with appropriate controls was available to calculate enrichment.
PM1
Not met: cancerhotspots.org reports no significant hotspot at SDHB codon 53, and Gly53 is not among the Fe-S cluster-binding cysteines.
PM2
Not met: allele frequency ~1.1% (Ashkenazi Jewish, gnomAD v4.1 and v2.1) far exceeds the <0.1% PM2 rarity threshold.
PM5
Not assessed: no alternate substitution at codon 53 with established pathogenicity was found; flagged for human review.
PM6
Not assessed: no reported de novo occurrence or parental testing result was available.
PP1
Not assessed: no informative relatives, genotypes, or segregation data were reported.
PP2
Not assessed: no gene-level missense-constraint metric or VCEP position on PP2 was available; flagged for human review.
PP3
Not met: REVEL 0.608 is below the PP3 supporting threshold (>=0.644) and above the BP4 threshold, an indeterminate zone.
PP4
Not assessed: no case-level phenotype was supplied to evaluate phenotype specificity.
PP5
Not met: no ClinVar expert-panel Pathogenic or Likely pathogenic assertion exists for this variant.
