Submissions for variant NM_000527.5(LDLR):c.1073G>A (p.Cys358Tyr)

dbSNP: rs875989915

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
LDLR-LOVD, British Heart Foundation	RCV000211603	SCV000295206	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	RCV000211603	SCV000503295	likely pathogenic	Hypercholesterolemia, familial, 1	2016-12-16	criteria provided, single submitter	clinical testing	subject mutated among 2600 FH index cases screened = 1 , family member = 1 / previously described in association with FH (linked to ethnicity ?) / Software predictions: Damaging
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	RCV000211603	SCV001433507	likely pathogenic	Hypercholesterolemia, familial, 1	2019-04-29	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001853402	SCV002246069	pathogenic	Familial hypercholesterolemia	2024-01-19	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 358 of the LDLR protein (p.Cys358Tyr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with familial hypercholesterolemia (PMID: 17142622, 21276076). This variant is also known as p.C337Y. ClinVar contains an entry for this variant (Variation ID: 226346). 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 with a positive predictive value of 95%. 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). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV002415886	SCV002717801	likely pathogenic	Cardiovascular phenotype	2021-08-06	criteria provided, single submitter	clinical testing	The p.C358Y variant (also known as c.1073G>A), located in coding exon 8 of the LDLR gene, results from a G to A substitution at nucleotide position 1073. The cysteine at codon 358, located in the EGF-like 2 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 has been detected in several individuals from familial hypercholesterolemia cohorts (Humphries SE et al. J Med Genet, 2006 Dec;43:943-9; Abifadel M et al. Hum Mutat, 2009 Jul;30:E682-91; Vladimirova-Kitova LG et al. Echocardiography, 2011 Feb;28:223-34). Internal structural analysis indicates this alteration eliminates a disulfide bond critical for the structural integrity of the EGF-like 2 domain (Ambry internal data). 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.
Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA - Fiona Stanley Hospital	RCV000211603	SCV000268599	pathogenic	Hypercholesterolemia, familial, 1	2015-07-03	no assertion criteria provided	clinical testing
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	RCV000211603	SCV000606321	pathogenic	Hypercholesterolemia, familial, 1		no assertion criteria provided	research