Submissions for variant NM_000527.5(LDLR):c.443G>A (p.Cys148Tyr)

dbSNP: rs879254526

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
LDLR-LOVD, British Heart Foundation	RCV000238228	SCV000294712	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	RCV000238228	SCV000503159	likely pathogenic	Hypercholesterolemia, familial, 1	2016-12-16	criteria provided, single submitter	clinical testing	subject mutated among 2600 FH index cases screened = 1
Department of Human Genetics, Laborarztpraxis Dres. Walther, Weindel und Kollegen	RCV000238228	SCV000987038	pathogenic	Hypercholesterolemia, familial, 1	2018-10-15	criteria provided, single submitter	clinical testing	The mutation occurs at protein level at position 148 (position 127 of the mature protein) to change the amino acid cysteine to tyrosine. This change has been reported in the literature, found in patients with familial hypercholesterolemia and is associated with elevated cholesterol and LDL-C levels. It leads to a disturbed LDLR transport from the endoplasmic reticulum to the cell surface or is partially retained in the endoplasmic reticulum (ER). We observed this mutation in a patient with TC up to 380 mg/dl and LDL-C approx 310 mg/dl at the age of 10 years. PMID: 16250003, 1301956, 11462246
Ambry Genetics	RCV002327174	SCV002632585	pathogenic	Cardiovascular phenotype	2023-07-05	criteria provided, single submitter	clinical testing	The c.443G>A (p.C148Y) alteration is located in exon 4 (coding exon 4) of the LDLR gene. This alteration results from a G to A substitution at nucleotide position 443, causing the cysteine (C) at amino acid position 148 to be replaced by a tyrosine (Y). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant (also referred to as C127Y) has been detected in several unrelated individuals with familial hypercholesterolemia (FH) and FH cohorts (Nauck, 2001; Fouchier, 2005; Humphries, 2006; Taylor, 2007; Moradi, 2021). Other variants affecting this codon, including c.443G>C (p.C148S), have also been reported in association with FH (Slimane, 2002). This amino acid position is highly conserved in available vertebrate species. 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, 2002). Internal structural analysis indicates this variant eliminates a disulfide bond critical for the structural integrity of LDLR class A repeat 4 (Ambry internal data). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV002518475	SCV003443865	pathogenic	Familial hypercholesterolemia	2024-03-29	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 148 of the LDLR protein (p.Cys148Tyr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with familial hypercholesterolemia (PMID: 11462246, 16389549, 17539906, 33732287). This variant is also known as C127Y. ClinVar contains an entry for this variant (Variation ID: 251225). 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.
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	RCV000238228	SCV000606120	pathogenic	Hypercholesterolemia, familial, 1		no assertion criteria provided	research
Rajaie Cardiovascular, Medical and Research Center, Iran University of Medical Sciences	RCV000238228	SCV001467722	pathogenic	Hypercholesterolemia, familial, 1		no assertion criteria provided	research