ClinVar

Description

Variant summary: LDLRAP1 c.605C>A (p.Ser202Tyr) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00084 in 1613942 control chromosomes in the gnomAD database, including 6 homozygotes. c.605C>A has been reported in the literature in multiple heterozygous individuals affected with or with clinical features of Familial Hypercholesterolemia, without strong evidence for causality, with frequent reporting as a VUS (e.g. Rubba_2017, Luirink_2019, Rieck_2020, Rimbert_2022). These reports do not provide unequivocal conclusions about association of the variant with Familial Hypercholesterolemia. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 25911074, 11326085, 30795984, 32770674, 35047021, 28353356). ClinVar contains an entry for this variant (Variation ID: 4776). Based on the evidence outlined above, the variant was classified as VUS-possibly benign.