ClinVar Miner

Submissions for variant NM_000527.5(LDLR):c.2389+1G>A

dbSNP: rs879255186
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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 RCV000238116 SCV000295969 likely pathogenic Hypercholesterolemia, familial, 1 2016-03-25 criteria provided, single submitter literature only
GeneDx RCV000657896 SCV000779660 pathogenic not provided 2021-03-30 criteria provided, single submitter clinical testing Identified in unrelated individuals with familial hypercholesterolemia (FH) in the published literature (Bertolini et al., 1999; Heath et al., 1999) and referred for dyslipidemia genetic testing at GeneDx; Not observed in large population cohorts (Lek et al., 2016); Canonical splice site variant expected to result in aberrant splicing, although in the absence of functional evidence the actual effect of this sequence change is unknown; This variant is associated with the following publications: (PMID: 10208479, 25525159, 18700895, 9974426, 32977124)
Invitae RCV002518498 SCV003442682 pathogenic Familial hypercholesterolemia 2022-07-23 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 16 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 is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individuals with familial hypercholesterolemia (PMID: 9974426, 10208479, 10735632, 32977124). This variant is also known as IVS16+1G>A, G>A+1 IVS16. ClinVar contains an entry for this variant (Variation ID: 252299). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.

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