ClinVar Miner

Submissions for variant NC_000019.9:g.(?_11212605)_(11217283_?)del

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV004581028 SCV005063572 pathogenic Familial hypercholesterolemia 2024-01-07 criteria provided, single submitter clinical testing This variant results in the deletion of exons 3-4 and part of exon 5 (c.191-735_737del) of the LDLR gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in LDLR are known to be pathogenic (PMID: 20809525, 28645073). This variant has been observed in individual(s) with clinical features of familial hypercholesterolemia (PMID: 34037665). ClinVar contains an entry for this variant (Variation ID: 948222). 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). For these reasons, this variant has been classified as Pathogenic.

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