Submissions for variant NM_000527.5(LDLR):c.827G>A (p.Cys276Tyr)

dbSNP: rs730882089

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
LDLR-LOVD, British Heart Foundation	RCV000237878	SCV000295003	likely pathogenic	Hypercholesterolemia, familial, 1	2016-03-25	criteria provided, single submitter	research
Ambry Genetics	RCV002429172	SCV002680171	likely pathogenic	Cardiovascular phenotype	2020-03-26	criteria provided, single submitter	clinical testing	The p.C276Y variant (also known as c.827G>A), located in coding exon 6 of the LDLR gene, results from a G to A substitution at nucleotide position 827. The cysteine at codon 276 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). Internal structural analysis indicates this alteration eliminates a disulfide bond critical for the structural integrity of LDLR class A repeat 7 (Ambry internal data). In addition, five different alterations located at the same amino acid position (p.C276F, p.C276S, p.C276R, p.C276G, p.C276W) have been detected in LDLR in families with hypercholesterolemia (Klanar G et al. J. Am. Coll. Cardiol., 2015 Sep;66:1250-1257; Thormaehlen AS et al. PLoS Genet., 2015 Feb;11:e1004855; Do R et al. Nature, 2015 Feb;518:102-6; Mozas P et al. Hum. Mutat., 2004 Aug;24:187; Bertolini S et al. Atherosclerosis, 2013 Apr;227:342-8; Martín-Campos JM et al. J Clin Lipidol 2018 Sep;12:1452-1462; Bertolini S et al. Arterioscler. Thromb. Vasc. Biol., 2000 Sep;20:E41-52; Deiana L et al. Arterioscler. Thromb. Vasc. Biol., 2000 Jan;20:236-43). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant was reported one time in population-based cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic.
GeneDx	RCV003228919	SCV003925904	pathogenic	not provided	2020-03-16	criteria provided, single submitter	clinical testing	Participates in disulfide bonding with another cysteine residue which is critical for correct protein structure, and is located in the LDL-receptor class A_ repeat domain which is necessary for ligand binding (Sudhof et al., 1985; Rudenko et al., 2002); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Reported in the Human Gene Mutation Database with hypercholesterolaemia (HGMD)
All of Us Research Program, National Institutes of Health	RCV000237878	SCV004839043	likely pathogenic	Hypercholesterolemia, familial, 1	2024-01-08	criteria provided, single submitter	clinical testing	This missense variant replaces cysteine with tyrosine at codon 276 in the LDLR type A repeat 7 of the LDLR protein. This variant is also known as p.Cys255Tyr in the mature protein. This variant alters a conserved cysteine residue that is critical for proper protein folding and function (PMID: 2088165, 6091915, 15952897). Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been observed in compound heterozygous state with a known pathogenic LDLR variant in one individual affected with severe homozygous familial hypercholesterolemia, a phenotype expected of having two deleterious LDLR variants (PMID: 36229885). Multiple different variants affecting the same codon (p.Cys276Gly, p.Cys276Trp, p.Cys276Arg, p.Cys276Ser), are considered to be disease-causing (ClinVar variation ID: 251480, 251482, 251479, 183096), suggesting that cysteine at this position is important for LDLR protein function. Based on the available evidence, this variant is classified as Likely Pathogenic.