ClinVar Miner

Submissions for variant NM_000527.5(LDLR):c.1061-2A>G

dbSNP: rs879254773
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
LDLR-LOVD, British Heart Foundation RCV000238241 SCV000295184 likely pathogenic Hypercholesterolemia, familial, 1 2016-03-25 criteria provided, single submitter literature only
Labcorp Genetics (formerly Invitae), Labcorp RCV001854899 SCV002246368 pathogenic Familial hypercholesterolemia 2024-05-23 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 7 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: 11472756, 17539906). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 251632). 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.
MGZ Medical Genetics Center RCV000238241 SCV002579566 pathogenic Hypercholesterolemia, familial, 1 2021-12-28 criteria provided, single submitter clinical testing
Institute of Human Genetics, University of Leipzig Medical Center RCV000238241 SCV005368393 pathogenic Hypercholesterolemia, familial, 1 2024-08-07 criteria provided, single submitter clinical testing Criteria applied: PVS1,PM2,PS4_SUP
GeneDx RCV004794380 SCV005414714 likely pathogenic not provided 2024-05-21 criteria provided, single submitter clinical testing Canonical splice site variant predicted to result in an in-frame loss of the adjacent exon in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Identified in patient and two affected relatives with FH, all of whom harbored a second variant on the same allele (PMID: 11472756) and in a patient referred for genetic testing at GeneDx; This variant is associated with the following publications: (PMID: 25525159, 11472756)

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