ClinVar Miner

Submissions for variant NM_000527.5(LDLR):c.695-1G>A

dbSNP: rs879254652
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Robarts Research Institute, Western University RCV000408837 SCV000484779 likely pathogenic Hypercholesterolemia, familial, 1 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV001217127 SCV001388958 pathogenic Familial hypercholesterolemia 2024-09-25 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 4 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: 21722902, 27765764). ClinVar contains an entry for this variant (Variation ID: 369859). 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.
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine RCV001217127 SCV001434986 likely pathogenic Familial hypercholesterolemia 2019-06-17 criteria provided, single submitter clinical testing This c.695-1G>A variant in the LDLR gene disrupts the canonical splice site and is predicted to result in abnormal splicing of LDLR mRNA. This variant is absent from general population databases. Therefore, this c.695-1G>A variant in the LDLR gene is classified as likely pathogenic.
Ambry Genetics RCV002365444 SCV002664363 pathogenic Cardiovascular phenotype 2022-08-11 criteria provided, single submitter clinical testing The c.695-1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide upstream from coding exon 5 of the LDLR gene. This variant has been detected in individuals from familial hypercholesterolemia (FH) cohorts or cohorts referred for FH genetic testing (Wang J et al. Arterioscler Thromb Vasc Biol, 2016 12;36:2439-2445; Kose E et al. J Pediatr Endocrinol Metab, 2020 Aug;33:1251-1256; Leren TP et al. Atherosclerosis, 2021 04;322:61-66; Sturm AC et al. JAMA Cardiol, 2021 08;6:902-909). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Another alteration impacting the same acceptor site (c.695-1G>C) has also been detected in individuals with LDL cholesterol levels consistent with FH (Ambry internal data). In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site and will result in the creation or strengthening of a novel splice acceptor site. 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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