Submissions for variant NM_000527.5(LDLR):c.1433G>A (p.Gly478Glu)

dbSNP: rs1555805380

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	RCV000508770	SCV002506345	likely pathogenic	Hypercholesterolemia, familial, 1	2022-01-31	reviewed by expert panel	curation	The NM_000527.4(LDLR):c.1433G>A (p.Gly478Glu) variant is classified as Likely pathogenic for Familial Hypercholesterolemia by applying evidence codes PM2, PM5, PP3 and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows: PM2 - This variant is absent from gnomAD (gnomAD v2.1.1), so PM2 is met. PM5 - 2 other missense variants in the same codon: (1) NM_000527.5(LDLR):c.1432G>A (p.Gly478Arg) - 1 star, Conflicting interpretations of pathogenicity: Likely pathogenic(8);Pathogenic(1);Uncertain significance(4) - Pathogenic by these guidelines (FH VCEP training Aug 2021) (2) NM_000527.5(LDLR):c.1432G>T (p.Gly478Trp) - 1 star, VUS in ClinVar - VUS by these guidelines --- there is 1 Pathogenic variant in the same codon, so PM5 is met. PP3 - REVEL = 0.984. It is above 0.75, so PP3 is met. PP4 - variant meets PM2 and was identified in 1 index case who fulfills Simon-Broome criteria from Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge, so PP4 is met
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	RCV000508770	SCV000606424	pathogenic	Hypercholesterolemia, familial, 1		no assertion criteria provided	research