ClinVar Miner

Submissions for variant NM_000527.5(LDLR):c.346T>C (p.Cys116Arg)

dbSNP: rs879254482
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
LDLR-LOVD, British Heart Foundation RCV000237774 SCV000294642 likely pathogenic Hypercholesterolemia, familial, 1 2016-03-25 criteria provided, single submitter literature only
Fundacion Hipercolesterolemia Familiar RCV000237774 SCV000607450 pathogenic Hypercholesterolemia, familial, 1 2016-03-01 criteria provided, single submitter research
Labcorp Genetics (formerly Invitae), Labcorp RCV001804973 SCV000816330 pathogenic Familial hypercholesterolemia 2021-07-26 criteria provided, single submitter clinical testing This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individuals affected with Familial Hypercholesterolemia (FH) (PMID: 11668640, 10634824), and in several other individuals collected as part of FH cohorts. However, it was unclear if the phenotype of these individuals met FH diagnostic thresholds (PMID: 10206683, 23375686, 15241806).  This variant is also known as C95R in the literature. ClinVar contains an entry for this variant (Variation ID: 251163). This variant affects a cysteine residue located within an epidermal-growth-factor (EGF)–like domain 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: 3495735, 4750422). In addition, missense substitutions within the LDLR EGF-like domains affecting cysteine residues are overrepresented among patients with hypercholesterolemia (PMID: 18325082). Experimental studies have shown that this missense change affects the binding ability of the LDLR protein (PMID:  25545329). For these reasons, this variant has been classified as Pathogenic. This sequence change replaces cysteine with arginine at codon 116 of the LDLR protein (p.Cys116Arg). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and arginine.
Color Diagnostics, LLC DBA Color Health RCV001804973 SCV002052110 likely pathogenic Familial hypercholesterolemia 2021-06-23 criteria provided, single submitter clinical testing This missense variant (also known as p.Cys95Arg in the mature protein) replaces cysteine with arginine at codon 116 of the LDLR protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Functional studies have shown that this variant disrupts LDL binding and uptake (PMID: 25545329). This variant has been reported in individuals affected with familial hypercholesterolemia (PMID: 10206683, 10634824, 11668640, 15241806, 19446849, 23375686, 32044282). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.

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