Submissions for variant NM_000527.5(LDLR):c.2042G>A (p.Cys681Tyr)

dbSNP: rs201637900

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
LDLR-LOVD, British Heart Foundation	RCV000238581	SCV000295835	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	RCV000238581	SCV000583921	pathogenic	Hypercholesterolemia, familial, 1	2017-03-30	criteria provided, single submitter	clinical testing
Invitae	RCV002229816	SCV000834842	likely pathogenic	Familial hypercholesterolemia	2018-06-01	criteria provided, single submitter	clinical testing	In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Variants that disrupt the p.Cys681 amino acid residue in LDLR have been observed in affected individuals (PMID: 18648394, 16092059, 9544745). This suggests that it is a clinically significant residue, and that other variants that disrupt this residue are likely to be causative of disease. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has been observed in several individuals affected with familial hypercholesterolemia (PMID: 7489239). This variant is also known as p.Cys660Tyr in the literature. ClinVar contains an entry for this variant (Variation ID: 252186) This variant is not present in population databases (ExAC no frequency). This sequence change replaces cysteine with tyrosine at codon 681 of the LDLR protein (p.Cys681Tyr). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and tyrosine. This variant affects a cysteine residue located within an epidermal-growth-factor (EGF)–like domain of the LDLR protein. Cysteine residues in these domains have been shown to be involved in the formation of disulfide bridges, which are critical for protein structure and stability (PMID: 3495735, 4750422). In addition, missense substitutions within the LDLR EGF-like domains affecting cysteine residues are overrepresented among patients with hypercholesterolemia (PMID: 18325082).
Ambry Genetics	RCV002418065	SCV002723063	likely pathogenic	Cardiovascular phenotype	2021-09-23	criteria provided, single submitter	clinical testing	The p.C681Y variant (also known as c.2042G>A), located in coding exon 14 of the LDLR gene, results from a G to A substitution at nucleotide position 2042. The cysteine at codon 681, located in the EGF-like 3 domain, 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 (also referred to as p.C660Y) has been detected in individuals from FH cohorts (Schuster H et al. Arterioscler Thromb Vasc Biol, 1995 Dec;15:2176-80; Humphries SE et al. J Med Genet, 2006 Dec;43:943-9; Tosi I et al. Atherosclerosis, 2007 Sep;194:102-11). Internal structural analysis indicates this alteration eliminates a disulfide bond critical for the structural integrity of the EGF-like 3 domain (Ambry internal data). Furthermore, other variants affecting this codon (e.g., p.C681S and p.C681W also referred to as p.C660S and p.C660W, respectively) have also been reported in association with FH (Chiu CY et al. Metabolism. 2005 Aug;54(8):1082-6; Sun XM et al. Atherosclerosis. 1998 Jan;136(1):175-85). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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.
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	RCV000238581	SCV000606581	pathogenic	Hypercholesterolemia, familial, 1		no assertion criteria provided	research