ClinVar

Description

The p.Arg3527Trp variant (also referred to in the literature as p.Arg3500Trp) in APOB has been reported in at least 33 individuals with familial hypercholesterolemia, the majority of whom are of East Asian ancestry, and segregated with disease in at least 15 affected relatives from 4 families (Gaffney 1995 PMID: 7627691, Choong 1997 PMID: 9191540, Tai 1998 PMID: 9702952, Fisher 1999 PMID: 10388479, Tai 2001 PMID: 11238294, Yang 2007 PMID: 17964958, Hollandt 2012 PMID: 22294733, Chiou 2010 PMID: 20538126, Chiou 2011 PMID: 21376320, Chiou 2012 PMID: 22353362, Bertolini 2013 PMID: 23375686). This variant has been reported in ClinVar (Variation ID 40223) and has also been identified in 0.12% (25/19946) of East Asian and 0.007% (25/128542) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). This frequency is low enough to be consistent with the frequency of familial hypercholesterolemia (FH) in the general population. In vitro functional studies provide some evidence that the p.Arg3527Trp variant may impact protein function (Gaffney 1995 PMID: 7627691, Fisher 1999 PMID: 10388479, Tai 2001 PMID: 11238294). Additionally, another variant at this position, p.Arg3527Gln, is a well-established pathogenic variant for FH. In summary, this variant meets criteria to be classified as pathogenic for FH in an autosomal dominant manner based upon segregation studies, increased prevalence in affected individuals, and pathogenicity of other variants at this position. Please note that pathogenic variants in APOB can have reduced penetrance and a less severe phenotype than disease-causing LDLR or PCSK9 variants (Youngblom and Knowles, GeneReviews, PMID: 24404629). ACMG/AMP Criteria applied: PS4_Strong; PP1_Strong, PS3_Supporting, PM5.