ClinVar Miner

Submissions for variant NM_000527.4(LDLR):c.1012T>A (p.Cys338Ser) (rs879254753)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
LDLR-LOVD, British Heart Foundation RCV000238172 SCV000295135 likely pathogenic Familial hypercholesterolemia 1 2016-03-25 criteria provided, single submitter literature only
Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge RCV000238172 SCV000599357 pathogenic Familial hypercholesterolemia 1 2016-03-01 criteria provided, single submitter curation
Invitae RCV000816844 SCV000957370 pathogenic Familial hypercholesterolemia 2018-12-28 criteria provided, single submitter clinical testing This sequence change replaces cysteine with serine at codon 338 of the LDLR protein (p.Cys338Ser). The cysteine residue is highly conserved and there is a moderate physicochemical difference between cysteine and serine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals affected with familial hypercholesterolemia (PMID: 8568489, 18718593, 10447263, 15241806, 28932795, 7583548). This variant is also known as FH-Wakayama and C317S in the literature. ClinVar contains an entry for this variant (Variation ID: 251592). 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.Cys338 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been observed in individuals with LDLR-related conditions (PMID: 10924730, 24420163, 10735632), suggesting that it is a clinically significant residue. As a result, variants that disrupt this residue are likely to be causative of disease. For these reasons, this variant has been classified as Pathogenic.

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