Submissions for variant NM_000527.5(LDLR):c.428G>A (p.Cys143Tyr)

dbSNP: rs879254522

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
LDLR-LOVD, British Heart Foundation	RCV000238346	SCV000294706	likely pathogenic	Hypercholesterolemia, familial, 1	2016-03-25	criteria provided, single submitter	literature only
Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix	RCV000238346	SCV000503156	likely pathogenic	Hypercholesterolemia, familial, 1	2016-12-16	criteria provided, single submitter	clinical testing	subject mutated among 2600 FH index cases screened = 1 / Software predictions: Damaging
U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille	RCV000238346	SCV000583675	pathogenic	Hypercholesterolemia, familial, 1	2017-03-30	criteria provided, single submitter	clinical testing
Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge	RCV000238346	SCV000599331	pathogenic	Hypercholesterolemia, familial, 1	2016-03-01	criteria provided, single submitter	curation
Ambry Genetics	RCV002327172	SCV002631814	pathogenic	Cardiovascular phenotype	2021-04-08	criteria provided, single submitter	clinical testing	The p.C143Y pathogenic mutation (also known as c.428G>A), located in coding exon 4 of the LDLR gene, results from a G to A substitution at nucleotide position 428. The cysteine at codon 143, located in LDLR class A repeat 3, 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 C122Y) has been detected in individuals reported to have FH (Genschel J et al. Hum Mutat, 2001 Apr;17:354; Dedoussis GV et al. Hum Mutat, 2004 Mar;23:285-6; Wang L et al. Nutr Metab Cardiovasc Dis, 2009 Jul;19:391-400; Kim HN et al. Chonnam Med J, 2018 Jan;54:31-35). Internal structural analysis indicates this alteration eliminates a disulfide bond critical for the structural integrity of LDLR class A repeat 3 (Ambry internal data). This variant was reported to result in defective LDLR binding ability in one in vitro study (Wang L et al. Nutr Metab Cardiovasc Dis, 2009 Jul;19:391-400). In addition, another alteration affecting this codon (p.C143F, c.428G>T) has also been reported in association with FH Gomez A et al. Atherosclerosis, 2019 12;291:44-51). This variant was not reported in population-based 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 supporting evidence, this alteration is interpreted as a disease-causing mutation.
PreventionGenetics, part of Exact Sciences	RCV003401202	SCV004103089	pathogenic	LDLR-related disorder	2023-08-31	criteria provided, single submitter	clinical testing	The LDLR c.428G>A variant is predicted to result in the amino acid substitution p.Cys143Tyr. This variant also described using legacy nomenclature as p.Cys122Tyr, has been documented in several reports as a causative variant for Hypercholesterolemia (Genschel et al. 2001. PubMed ID: 11295843; Cao et al. 2003. PubMed ID: 14570618; Dedoussis et al. 2004. PubMed ID: 14974088; Wang et al. 2008. PubMed ID: 19073363; Kim et al. 2018. PubMed ID: 29399563). Functional study showed that this variant results in defective LDLR binding ability (Wang et al. 2008. PubMed ID: 19073363). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. In ClinVar, this variant is interpreted as pathogenic or likely pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/251220/). This variant is interpreted as pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV003581597	SCV004298316	pathogenic	Familial hypercholesterolemia	2023-10-08	criteria provided, single submitter	clinical testing	This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 143 of the LDLR protein (p.Cys143Tyr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with familial hypercholesterolemia (PMID: 11295843, 14974088, 19073363). This variant is also known as C122Y. ClinVar contains an entry for this variant (Variation ID: 251220). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt LDLR protein function. This variant affects a cysteine residue located within an LDLRA or epidermal-growth-factor (EGF)-like domains 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: 7548065, 7603991, 7979249). In addition, missense substitutions within the LDLRA and EGF-like domains affecting cysteine residues are overrepresented among patients with hypercholesterolemia (PMID: 18325082). This variant disrupts the p.Cys143 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 28964736, 30592178, 34040191). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.