Submissions for variant NM_000527.5(LDLR):c.1019G>A (p.Cys340Tyr)

dbSNP: rs755757866

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
LDLR-LOVD, British Heart Foundation	RCV000237709	SCV000295143	likely pathogenic	Hypercholesterolemia, familial, 1	2016-03-25	criteria provided, single submitter	literature only
Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation	RCV000237709	SCV000540782	likely pathogenic	Hypercholesterolemia, familial, 1	2016-11-05	criteria provided, single submitter	clinical testing	Disrupt disulfide bridge between Cys340 and Cys352.
Fundacion Hipercolesterolemia Familiar	RCV000237709	SCV000607545	uncertain significance	Hypercholesterolemia, familial, 1	2016-03-01	criteria provided, single submitter	research
Color Diagnostics, LLC DBA Color Health	RCV000775249	SCV000909507	likely pathogenic	Familial hypercholesterolemia	2020-03-25	criteria provided, single submitter	clinical testing	This missense variant (also known as p.Cys319Tyr in the mature protein) replaces cysteine with tyrosine at codon 340 of the LDLR protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Although functional studies have not been performed for this variant, it changes one of the functionally critical cysteine residues that form intra-repeat disulfide bonds in the EGF precursor homology domain (PMID: 3495735, 4750422) and is expected to have deleterious impact on the LDLR protein folding and stability. This variant has been reported in multiple individuals diagnosed with familial hypercholesterolemia (PMID: 15241806, 27824480). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.
Invitae	RCV000775249	SCV002211499	pathogenic	Familial hypercholesterolemia	2024-01-21	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 340 of the LDLR protein (p.Cys340Tyr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with familial hypercholesterolemia (PMID: 27824480, 30592178). ClinVar contains an entry for this variant (Variation ID: 251600). 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	RCV002365245	SCV002659632	pathogenic	Cardiovascular phenotype	2022-03-25	criteria provided, single submitter	clinical testing	The p.C340Y pathogenic mutation (also known as c.1019G>A), located in coding exon 7 of the LDLR gene, results from a G to A substitution at nucleotide position 1019. The cysteine at codon 340, located in the EGF-like 1 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 variant (also referred to as p.C319Y) has been detected in several individuals with familial hypercholesterolemia (FH) or from FH cohorts (Mozas P et al. Hum Mutat, 2004 Aug;24:187; Gabová D et al. Physiol Res, 2017 03;66:75-84; Chan ML et al. Mol Genet Genomic Med, 2019 02;7:e00520). Internal structural analysis indicates this alteration eliminates a disulfide bond critical for the structural integrity of the EGF-like 1 domain (Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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.