ClinVar Miner

Submissions for variant NM_000527.4(LDLR):c.1187-2A>G (rs879254823)

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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 RCV000237447 SCV000295274 likely pathogenic Familial hypercholesterolemia 2016-03-25 criteria provided, single submitter literature only
GeneDx RCV000482482 SCV000568522 pathogenic not provided 2017-03-13 criteria provided, single submitter clinical testing The c.1187-2 A>G variant has been reported in the heterozygous state in one Norwegian proband with FH (Holla et al., 2009). This variant destroys the canonical splice acceptor site located at the intron 8/exon 9 junction, and is predicted to cause abnormal gene splicing. This variant is predicted to lead to an abnormal message that is subject to nonsense-mediated mRNA decay, consistent with comprehensive mRNA splicing studies determined by wet-lab analyses in the same study by Holla et al. (2009). In addition, other downstream splice site variants in the LDLR gene have been reported in HGMD in association with FH (Stenson et al., 2014), indicating that loss of function is a known disease mechanism. Furthermore, the c.1187-2 A>G variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). In summary, c.1187-2 A>G in the LDLR gene is interpreted as a pathogenic variant.
Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge RCV000237447 SCV000599366 pathogenic Familial hypercholesterolemia 2016-03-01 criteria provided, single submitter curation

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