ClinVar Miner

Submissions for variant NM_000527.5(LDLR):c.1587-1G>A

dbSNP: rs879254948
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
LDLR-LOVD, British Heart Foundation RCV000238178 SCV000295525 likely pathogenic Hypercholesterolemia, familial, 1 2016-03-25 criteria provided, single submitter literature only
Color Diagnostics, LLC DBA Color Health RCV001183447 SCV001349167 pathogenic Familial hypercholesterolemia 2023-03-29 criteria provided, single submitter clinical testing This variant also known as IVS10-1G>A) causes a G to A nucleotide substitution at the -1 position of intron 10 of the LDLR gene. Splice site prediction tools suggest that this variant may have a significant impact on RNA splicing. Although this prediction has not been confirmed in published RNA studies, this variant is expected to result in an absent or disrupted protein product. This variant has been reported in over 10 unrelated individuals affected with familial hypercholesterolemia (PMID: 12417285, 27680772, 32044282). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of LDLR function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.
Invitae RCV001183447 SCV002157577 pathogenic Familial hypercholesterolemia 2023-12-04 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 10 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: 12417285, 26361156, 27680772). ClinVar contains an entry for this variant (Variation ID: 251922). 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.
Ambry Genetics RCV002401939 SCV002708332 pathogenic Cardiovascular phenotype 2021-03-30 criteria provided, single submitter clinical testing The c.1587-1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide upstream from coding exon 11 of the LDLR gene. This alteration has been reported in several subjects with familial hypercholesterolemia (Yu W et al. Atherosclerosis, 2002 Dec;165:335-42; Martin R et al. Atherosclerosis, 2016 Nov;254:8-13). In addition to the clinical data presented in the literature, alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as a disease-causing mutation.

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