ClinVar Miner

Submissions for variant NM_000527.5(LDLR):c.1102T>C (p.Cys368Arg)

dbSNP: rs879254791
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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Robarts Research Institute, Western University RCV000408876 SCV000484748 likely pathogenic Hypercholesterolemia, familial, 1 criteria provided, single submitter clinical testing
U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille RCV000408876 SCV000583788 pathogenic Hypercholesterolemia, familial, 1 2017-03-30 criteria provided, single submitter clinical testing
Invitae RCV002230212 SCV000818723 pathogenic Familial hypercholesterolemia 2023-12-20 criteria provided, single submitter clinical testing This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 368 of the LDLR protein (p.Cys368Arg). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This missense change has been observed in individuals with familial hypercholesterolemia (PMID: 9452094, 27765764). It has also been observed to segregate with disease in related individuals. This variant is also known as p.Cys347Arg. ClinVar contains an entry for this variant (Variation ID: 369848). 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). This variant disrupts the p.Cys368 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been observed in individuals with LDLR-related conditions (PMID: 1310940, 9452094, 15823276, 21722902, 23064986, 25461735, 26081744, 27765764), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute RCV000408876 SCV000987459 pathogenic Hypercholesterolemia, familial, 1 criteria provided, single submitter clinical testing
Brunham Lab, Centre for Heart and Lung Innovation, University of British Columbia RCV000408876 SCV001432591 pathogenic Hypercholesterolemia, familial, 1 2019-05-10 criteria provided, single submitter research
GeneDx RCV002275000 SCV002562549 likely pathogenic not provided 2022-02-03 criteria provided, single submitter clinical testing Located within the LDL-receptor EGF precursor domain 2, and participates in disulfide bonding with another cysteine residue which is critical for correct protein structure; Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 32041611, 34037665, 27765764, 9452094)
Ambry Genetics RCV002429335 SCV002742917 pathogenic Cardiovascular phenotype 2021-02-09 criteria provided, single submitter clinical testing The p.C368R pathogenic mutation (also known as legacy p.C347R and c.1102T>C), located in coding exon 8 of the LDLR gene, results from a T to C substitution at nucleotide position 1102. The cysteine at codon 368 is replaced by arginine, 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 particular cysteine alteration has been reported in individuals with familial hypercholesterolemia, including one French Canadian family showing segregation with disease in the proband and two affected family members (Couture P et al. Hum Mutat, 1998;Suppl 1:S226-31; Drouin-Chartier JP et al. Metabolism, 2015 Nov;64:1541-7; Wang J et al. Arterioscler Thromb Vasc Biol, 2016 12;36:2439-2445; Garg A et al. J Endocr Soc, 2020 Jan;4:bvz015). Internal structural analysis indicates this alteration eliminates a disulfide bond critical for the structural integrity of the EGF-like 2 domain (Ambry internal data). This allele was reported in one heterozygous individual in population-based cohorts in the Genome Aggregation Database (gnomAD). In addition, this alteration is predicted to be deleterious by in silico analysis. Two other alterations at the same codon, p.C368Y (legacy p.C347Y, c.1103G>A) and p.C368G (legacy p.C347G, c.1102T>G), have been detected in individuals with hypercholesterolemia (Loux N et al. Hum. Mutat., 1992;1:325-32; Sözen MM et al. Atherosclerosis, 2005 May;180:63-71). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum RCV000408876 SCV000606327 pathogenic Hypercholesterolemia, familial, 1 no assertion criteria provided research

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