Submissions for variant NM_000527.5(LDLR):c.1013G>A (p.Cys338Tyr)

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
LDLR-LOVD, British Heart Foundation	RCV000238118	SCV000295138	likely pathogenic	Hypercholesterolemia, familial, 1	2016-03-25	criteria provided, single submitter	literature only
Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation	RCV000238118	SCV000540781	likely pathogenic	Hypercholesterolemia, familial, 1	2016-11-05	criteria provided, single submitter	clinical testing	Disrupt disulfide bridge between Cys325 and Cys338.
Laboratory of Genetics and Molecular Cardiology, University of São Paulo	RCV000238118	SCV000588538	pathogenic	Hypercholesterolemia, familial, 1	2016-03-01	criteria provided, single submitter	research
Invitae	RCV002229814	SCV000814222	pathogenic	Familial hypercholesterolemia	2023-06-05	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Cys338 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been observed in individuals with LDLR-related conditions (PMID: 8568489, 10735632, 10924730, 24420163), which suggests that this may be a clinically significant amino acid residue. 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). Experimental studies have shown that this missense change affects LDLR function (PMID: 10924730). 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. ClinVar contains an entry for this variant (Variation ID: 251595). This variant is also known as p.C317T. This missense change has been observed in individual(s) with familial hypercholesterolemia (PMID: 10924730). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 338 of the LDLR protein (p.Cys338Tyr).
Mayo Clinic Laboratories, Mayo Clinic	RCV001843948	SCV002103276	pathogenic	not provided	2021-05-13	criteria provided, single submitter	clinical testing	PM1, PM5, PM2, PM3_supporting, PS3_supporting, PP3, PP1
Ambry Genetics	RCV002374404	SCV002625208	pathogenic	Cardiovascular phenotype	2018-01-02	criteria provided, single submitter	clinical testing	The p.C338Y pathogenic mutation (also known as c.1013G>A), located in coding exon 7 of the LDLR gene, results from a G to A substitution at nucleotide position 1013. The cysteine at codon 338 is replaced by tyrosine, an amino acid with highly dissimilar properties. This alteration has been reported in individuals with familial hypercholesterolemia (FH), and reduced LDL binding was demonstrated in a study of patient skin fibroblasts (Nauck MS et al. Atherosclerosis, 2000;151:525-34; Dušková L et al. Atherosclerosis, 2011;216:139-45). 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 FH (Villéger L et al. Hum Mutat. 2002;20(2):81-7). Internal structural analysis indicates this alteration eliminates a disulfide bond critical for the structural integrity of the EGF-like 1 domain (Rudenko G et al. Science. 2002;298(5602):2353-8). In addition, alterations at the same amino acid position (C338G, C338R, and C338S) have also been reported in association with FH (Lombardi MP et al. Clin. Genet., 2000;57:116-24; Varret M et al. Nucleic Acids Res., 1998;26:248-52; Maruyama T et al. Arterioscler. Thromb. Vasc. Biol., 1995;15:1713-8). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Illumina Laboratory Services, Illumina	RCV000238118	SCV004101320	likely pathogenic	Hypercholesterolemia, familial, 1	2023-08-28	criteria provided, single submitter	clinical testing	The LDLR c.1013G>A (p.Cys338Tyr) missense variant results in the substitution of cysteine at amino acid position 338 with tyrosine. This variant has been identified in individuals with a phenotype consistent with familial hypercholesterolemia, and has been shown to segregate with disease (PMID: 10924730; 34037665). A functional study conducted in patient cells demonstrated that this variant impacts protein function (PMID: 10924730). This variant affects one of 60 highly conserved cysteine residues that are critical for protein folding and function (PMID: 34906454). This variant is not observed in version 2.1.1 or version 3.1.2 of the Genome Aggregation Database. Multiple lines of computational evidence suggest the variant may impact the gene or gene product. Based on the available evidence, the c.1013G>A (p.Cys338Tyr) variant is classified as likely pathogenic for familial hypercholesterolemia.