ClinVar Genomic variation as it relates to human health

This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 379 of the LDLR protein (p.Cys379Arg). This variant is present in population databases (no rsID available, gnomAD 0.007%). This missense change has been observed in individuals with hypercholesterolemia (PMID: 9852677, 11317362, 15241806, 23375686, 25682026). It has also been observed to segregate with disease in related individuals. This variant is also known as FH Naples-1 and C358R. ClinVar contains an entry for this variant (Variation ID: 251685). 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%. Experimental studies have shown that this missense change affects LDLR function (PMID: 1301956, 21865347). For these reasons, this variant has been classified as Pathogenic.

Reduced activity, in stimulated T-lymphocytes and EBV-transformed B-lymphocytes.

PS4, PS3, PM2, PP3

PS3, PP3, PM5, PS4, PM2_SUP

Identified in a patient with early-onset myocardial infarction in published literature (Khera et al., 2019); Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies demonstrate a significant reduction in LDL receptor activity (Hobbs et al., 1992); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as p.(C358R); This variant is associated with the following publications: (PMID: 1301956, 34037665, 32759540, 33955087, 30710474, 34040191, 32220565, 26723464, 35379577, 30586733, 32977124, 23375686, 21865347)

This missense variant (also known as p.Cys358Arg in the mature protein) replaces cysteine with arginine at codon 379 in the EGF-like repeat B of the LDLR protein. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies using patient-derived fibroblasts have shown that this variant causes a significant reduction in LDLR activity in the homozygous state (PMID: 1301956, 9974426). Another functional study using heterozygous patient-derived lymphocytes has shown that this variant causes a significant reduction in residual LDLR activity compared to wild-type (PMID: 21865347). This variant has been reported in over 10 individuals affected with familial hypercholesterolemia (PMID: 11317362, 15241806, 17196209, 25682026, 26342331, 30710474, 32759540, 33955087, 34037665). This variant has also been observed in compound heterozygous and homozygous state in individuals affected with homozygous familial hypercholesterolemia (PMID: 9974426, 1301956, 9974426, 11317362, 15823276, 23375686, 26723464, 27578108, 32977124), indicating that this variant contributes to disease. This variant has been identified in 1/31396 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic.

The LDLR c.1135T>C; p.Cys379Arg variant (rs879254803), also known as Cys358Arg in legacy nomenclature, is reported in the literature in the heterozygous, homozygous and compound heterozygous sates in numerous individuals affected with familial hypercholesterolemia (Bertolini 2020, Campagna 2008, Hobbs 1992, Sozen 2005, Wang 2020). Fibroblasts/ lymphocytes isolated from homozygous and heterozygous individuals have significantly reduced LDLR activity (Liguori 2001, Romano 2011). This variant is also reported in ClinVar (Variation ID: 251685) and is only observed on one allele in the Genome Aggregation Database, indicating it is not a common polymorphism. The cysteine at codon 379 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.985). Based on available information, this variant is considered to be pathogenic. References: Bertolini S et al. Homozygous familial hypercholesterolemia in Italy: Clinical and molecular features. Atherosclerosis. 2020 Nov;312:72-78. PMID: 32977124. Campagna F et al. Detection of familial hypercholesterolemia in a cohort of children with hypercholesterolemia: results of a family and DNA-based screening. Atherosclerosis. 2008 Jan;196(1):356-364. PMID: 17196209. Hobbs HH et al. Molecular genetics of the LDL receptor gene in familial hypercholesterolemia. Hum Mutat. 1992;1(6):445-66. PMID: 1301956. Liguori R et al. LDL receptor cDNA sequence analysis in familial hypercholesterolemia patients: 5 novel mutations with high prevalence in families originating from southern Italy. Hum Mutat. 2001 May;17(5):433. PMID: 11317362. Romano M et al. An improved method on stimulated T-lymphocytes to functionally characterize novel and known LDLR mutations. J Lipid Res. 2011 Nov;52(11):2095-100. PMID: 21865347. Sozen MM et al. The molecular basis of familial hypercholesterolaemia in Turkish patients. Atherosclerosis. 2005 May;180(1):63-71. PMID: 15823276. Wang H et al. Targeted Genetic Analysis in a Chinese Cohort of 208 Patients Related to Familial Hypercholesterolemia. J Atheroscler Thromb. 2020 Dec 1;27(12):1288-1298. PMID: 32759540.

This missense variant (also known as p.Cys358Arg in the mature protein) replaces cysteine with arginine at codon 379 in the EGF-like repeat B of the LDLR protein. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies using patient-derived fibroblasts have shown that this variant causes a significant reduction in LDLR activity in the homozygous state (PMID: 1301956, 9974426). Another functional study using heterozygous patient-derived lymphocytes has shown that this variant causes a significant reduction in residual LDLR activity compared to wild-type (PMID: 21865347). This variant has been reported in over 10 individuals affected with familial hypercholesterolemia (PMID: 11317362, 15241806, 17196209, 25682026, 26342331, 30710474, 32759540, 33955087, 34037665). This variant has also been observed in compound heterozygous and homozygous state in individuals affected with homozygous familial hypercholesterolemia (PMID: 9974426, 1301956, 9974426, 11317362, 15823276, 23375686, 26723464, 27578108, 32977124), indicating that this variant contributes to disease. This variant has been identified in 1/31396 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic.

The p.C379R pathogenic mutation (also known as c.1135T>C), located in coding exon 8 of the LDLR gene, results from a T to C substitution at nucleotide position 1135. The cysteine at codon 379 is replaced by arginine, an amino acid with highly dissimilar properties, and is located in the EGF-like B domain. This alteration (with legacy nomenclature p.C358R and FH Naples-1) has been reported in the heterozygous, compound heterozygous, and homozygous states in multiple unrelated individuals with familial hypercholesterolemia (FH) (e.g., Liguori R et al. Hum. Mutat. 2001;17:433; Sözen MM et al. Atherosclerosis. 2005;180:63-71; Campagna F et al. Atherosclerosis. 2008;196:356-64). Fibroblasts derived from several unrelated patients homozygous for this alteration exhibit 15-30% of normal LDLR activity, and lymphocytes obtained from a heterozygous patient also show reduced LDLR activity (Hobbs HH et al. Hum. Mutat. 1992;1:445-66; Bertolini S et al. Arterioscler. Thromb. Vasc. Biol. 1999;19:408-18; Romano M et al. J. Lipid Res. 2011;52:2095-100). Internal structural analysis indicates that this alteration disrupts a disulfide bond known to be crucial for the structural stability of the region (Ambry internal data). 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). In addition, a variant at the same codon, p.C379Y, has also been associated with FH (Hirayama T et al. J. Hum. Genet. 1998;43:250-4). In addition, this alteration is predicted to be deleterious by BayesDel in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.