ClinVar Miner

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

dbSNP: rs879254522
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Total submissions: 7
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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 condition 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.
Invitae 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.

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