ClinVar Miner

Submissions for variant NM_000527.5(LDLR):c.245G>A (p.Cys82Tyr)

dbSNP: rs879254448
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
LDLR-LOVD, British Heart Foundation RCV000237958 SCV000294551 likely pathogenic Hypercholesterolemia, familial, 1 2016-03-25 criteria provided, single submitter literature only
U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille RCV000237958 SCV000583642 pathogenic Hypercholesterolemia, familial, 1 2017-03-30 criteria provided, single submitter clinical testing
Ambry Genetics RCV002429165 SCV002731637 likely pathogenic Cardiovascular phenotype 2019-01-03 criteria provided, single submitter clinical testing The p.C82Y variant (also known as c.245G>A), located in coding exon 3 of the LDLR gene, results from a G to A substitution at nucleotide position 245. The cysteine at codon 82, located in LDLR class A repeat 2, is replaced by tyrosine, an amino acid with highly dissimilar properties. Pathogenic LDLR mutations that result in the substitution or generation of cysteine residues within the cysteine-rich LDLR class A repeats and EGF-like domains are common in familial hypercholesterolemia (FH) (Villéger L. Hum Mutat. 2002;20(2):81-7). This particular cysteine alteration (referred to as C61Y) has been detected in a hypercholesterolemia cohort; however, clinical details were limited (Weiss N et al. J. Inherit. Metab. Dis. 2000 Dec;23:778-90). Internal structural analysis indicates this alteration eliminates a disulfide bond critical for the structural integrity of LDLR class A repeat 2 (Ambry internal data). In addition, several other variants affecting this codon (p.C82F (c.245G>T), p.C82G (c.244T>G), and p.C82S (c.245G>C)) have also been detected in association with hypercholesterolemia (Yu W et al. Atherosclerosis. 2002 Dec;165:335-42; Marduel M et al. Hum. Mutat. 2010 Nov;31:E1811-24; Jannes CE et al. Atherosclerosis. 2015 Jan;238:101-7). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.

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