Submissions for variant NM_000527.5(LDLR):c.1091G>A (p.Cys364Tyr)

dbSNP: rs879254788

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Robarts Research Institute, Western University	RCV000408761	SCV000484766	likely pathogenic	Hypercholesterolemia, familial, 1		criteria provided, single submitter	clinical testing
Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation	RCV000408761	SCV000540792	likely pathogenic	Hypercholesterolemia, familial, 1	2016-11-05	criteria provided, single submitter	clinical testing	Disrupt disulfide bridge between Cys364 and Cys377.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001861358	SCV002240775	pathogenic	Familial hypercholesterolemia	2020-12-29	criteria provided, single submitter	clinical testing	This sequence change replaces cysteine with tyrosine at codon 364 of the LDLR protein (p.Cys364Tyr). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and tyrosine. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant disrupts the p.Cys364 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 1301956, 23375686, 26723464, 21722902, 25461735, 16314194, 10978268, 15556094). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with familial hypercholesterolemia (PMID: 31153816, 29353225, 27765764, 28379029). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 369852). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV004639228	SCV005136020	likely pathogenic	Cardiovascular phenotype	2024-06-12	criteria provided, single submitter	clinical testing	The p.C364Y variant (also known as c.1091G>A), located in coding exon 8 of the LDLR gene, results from a G to A substitution at nucleotide position 1091. The cysteine at codon 364 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). Internal structural analysis indicates this variant eliminates a disulfide bond critical for the structural integrity of the EGF-like 2 domain (Ambry internal data). This alteration, which is also known as p.C343Y, has been reported in individuals with FH (Wang J et al. Arterioscler Thromb Vasc Biol, 2016 Dec;36:2439-2445; Tichý L et al. Physiol Res, 2017 Apr;66:S47-S54; Pek SLT et al. Atherosclerosis, 2018 Feb;269:106-116; Sánchez-Hernández RM et al. J Clin Lipidol, 2019 May;13:618-626). Another variant at the same codon, p.C364R (c.1090T>C), has been detected in conjunction with another alteration in the LDLR gene in an individual whose protein activity was 15-30% of normal (Hobbs HH et al. Hum Mutat. 1992;1(6):445-66), and subsequent studies have reported this alteration in several individuals diagnosed with FH (Bertolini S et al. Arterioscler Thromb Vasc Biol. 2000;20(9):E41-52). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic.