ClinVar Miner

Submissions for variant NM_000527.5(LDLR):c.610T>C (p.Cys204Arg)

dbSNP: rs1057519655
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV001973440 SCV002260284 likely pathogenic Familial hypercholesterolemia 2021-10-25 criteria provided, single submitter clinical testing In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Cys204 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been observed in individuals with LDLR-related conditions (PMID: 22881376, 23375686, 30592178), 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). 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. This missense change has been observed in individuals with familial hypercholesterolemia (PMID: 30592178; Invitae). This variant is present in population databases (no rsID available, gnomAD 0.003%). This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 204 of the LDLR protein (p.Cys204Arg).
Ambry Genetics RCV002352683 SCV002660522 pathogenic Cardiovascular phenotype 2024-05-28 criteria provided, single submitter clinical testing The p.C204R pathogenic mutation (also known as c.610T>C), located in coding exon 4 of the LDLR gene, results from a T to C substitution at nucleotide position 610. The cysteine at codon 204 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). Internal structural analysis indicates this variant eliminates a disulfide bond critical for the structural integrity of the LDLR class A repeat 5 (Ambry internal data). This particular cysteine alteration has been detected in an individual from a FH cohort (Chan ML et al. Mol Genet Genomic Med, 2019 02;7:e00520). Another variant at the same codon, p.C204Y (c.611G>A), has been described in individuals with FH (Cefalù AB et al. Int. J. Mol. Med., 2006 Mar;17:539-46; Marduel M et al. Hum. Mutat., 2010 Nov;31:E1811-24; Bertolini S et al. Atherosclerosis, 2013 Apr;227:342-8). 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.

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