ClinVar Miner

Submissions for variant NM_000527.4(LDLR):c.68-1G>C (rs879254397)

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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 RCV000238079 SCV000294449 pathogenic Familial hypercholesterolemia 2016-03-25 criteria provided, single submitter literature only
Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge RCV000238079 SCV000599310 pathogenic Familial hypercholesterolemia 2016-03-01 criteria provided, single submitter curation
GeneDx RCV000521979 SCV000617498 pathogenic not provided 2017-10-23 criteria provided, single submitter clinical testing The c.68-1 G>C variant in the LDLR gene has been identified in a homozygous state in one individual with severe hypercholesterolemia and tendon xnathomas. Three maternal relatives were heterozygous for the variant and had serum choleterol levels consistent with heterozygous FH (HeFH). Cultured fibroblasts from the proband showed null LDLR protein synthesis. Additionally, functional mRNA studies supported destruction of the canonical splice acceptor site in intron 1, and utilization of a cryptic acceptor site downstream of exon 2 (Maruyama et al. 1998). This variant was also published in an individual with clinical HeFH, who also harbored a rare variant in the PCSK9 gene (Ohta et al., 2016). This variant is predicted to lead to either an abnormal message that is subject to nonsense-mediated mRNA decay, or to an abnormal protein product if the message is used for protein translation. Other splice site variants in the LDLR gene, including c.68-2 A>T and c.68-2 A>G, have been reported in HGMD in association with FH (Stenson et al., 2014). Furthermore, the c.68-1 G>C variant is not observed in large population cohorts (Lek et al., 2016).

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