ClinVar Miner

Submissions for variant NM_000527.5(LDLR):c.817+1G>A

dbSNP: rs879254685
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
LDLR-LOVD, British Heart Foundation RCV000237841 SCV000294991 likely pathogenic Hypercholesterolemia, familial, 1 2016-03-25 criteria provided, single submitter literature only
Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation RCV000237841 SCV000540762 pathogenic Hypercholesterolemia, familial, 1 2016-11-05 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001193787 SCV001362898 pathogenic Familial hypercholesterolemia 2019-09-30 criteria provided, single submitter clinical testing Variant summary: LDLR c.817+1G>A is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Five predict the variant abolishes a 5' splicing donor site. These predictions are supported by a functional study, Vandrovcova_2013, that found the variant to affect splicing. The variant was absent in 251430 control chromosomes (gnomAD). c.817+1G>A has been reported in the literature in multiple individuals affected with Familial Hypercholesterolemia including a homozygous individual (Duskova_2011, Hu_2016, Vandrovcova_2013, Chiou_2017, Lin_2004). These data indicate that the variant is very likely to be associated with disease. Three ClinVar submissions (evaluation after 2014) cite the variant twice as pathogenic and once as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae RCV001193787 SCV001373984 pathogenic Familial hypercholesterolemia 2023-05-01 criteria provided, single submitter clinical testing Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 251469). Disruption of this splice site has been observed in individuals with familial hypercholesterolemia (PMID: 21310417, 23680767, 26875521). This variant is not present in population databases (gnomAD no frequency). This sequence change affects a donor splice site in intron 5 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). For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics, Fulgent Genetics RCV000237841 SCV002792056 pathogenic Hypercholesterolemia, familial, 1 2021-10-16 criteria provided, single submitter clinical testing
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum RCV000237841 SCV000606234 pathogenic Hypercholesterolemia, familial, 1 no assertion criteria provided research

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