ClinVar Miner

Submissions for variant NM_000527.5(LDLR):c.706T>A (p.Cys236Ser)

dbSNP: rs879254655
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Fundacion Hipercolesterolemia Familiar RCV000509412 SCV000607497 uncertain significance Hypercholesterolemia, familial, 1 2016-03-01 criteria provided, single submitter research
Labcorp Genetics (formerly Invitae), Labcorp RCV001857296 SCV002186728 uncertain significance Familial hypercholesterolemia 2021-11-23 criteria provided, single submitter clinical testing This variant is not present in population databases (gnomAD no frequency). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. 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 sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 441192). This missense change has been observed in individual(s) with clinical features of familial hypercholesterolemia (PMID: 28475941; Invitae). This sequence change replaces cysteine, which is neutral and slightly polar, with serine, which is neutral and polar, at codon 236 of the LDLR protein (p.Cys236Ser).

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