ClinVar Miner

Submissions for variant NM_000527.5(LDLR):c.313+2T>C (rs793888517)

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Total submissions: 15
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Institute for Integrative and Experimental Genomics,University of Luebeck RCV000172957 SCV000212132 likely benign Familial hypercholesterolemia 1 criteria provided, single submitter research
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000844755 SCV000271390 pathogenic Homozygous familial hypercholesterolemia 2017-10-02 criteria provided, single submitter clinical testing The c.313+2T>C variant in LDLR has been reported in 10 individuals with familial hypercholesterolemia (Lombardi 1995, Nauck 2001, Amsellem 2002, Graham 2005, Br usgaard 2006, Braenne 2015). This variant reportedly did not segregate with elev ated LDL cholesterol levels in 2 relatives from 1 family although the authors li st a second variant in both affected family members (Braenne 2015). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID 189296) and was absent from large population studies. The c.313+2T>C variant occ urs in the invariant region (+/- 1,2) of the splice consensus sequence and is pr edicted to cause altered splicing leading to an abnormal or absent protein. Hete rozygous loss of LDLR function is an established disease mechanism in familial h ypercholesterolemia. Of note, 2 other prevalent, pathogenic variants have been reported in association with FH at this splice site (c.313+1G>A and c.313+1G>C) in our laboratory, supporting pathogenicity of the c.313+2T>C variant. In summar y, this variant meets criteria to be classified as pathogenic for familial hyper cholesterolemia in an autosomal dominant manner based upon the predicted impact to the protein, presence in multiple affected individuals and absence from the g eneral population.
LDLR-LOVD, British Heart Foundation RCV000172957 SCV000294609 likely pathogenic Familial hypercholesterolemia 1 2016-03-25 criteria provided, single submitter literature only
Robarts Research Institute,Western University RCV000172957 SCV000484778 likely pathogenic Familial hypercholesterolemia 1 criteria provided, single submitter clinical testing
Invitae RCV000771312 SCV000544667 pathogenic Familial hypercholesterolemia 2020-09-27 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 3 of the LDLR gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is not present in population databases (rs793888517, ExAC no frequency). This variant has been reported in multiple unrelated individuals affected with familial hypercholesterolemia (PMID: 7616128, 11462246, 14974088, 16542394, 21475731). ClinVar contains an entry for this variant (Variation ID: 189296). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may alter RNA splicing, but this prediction has not been confirmed by published transcriptional studies. In summary, donor and acceptor splice site variants are typically loss-of-function (PMID: 16199547), and loss-of-function variants in LDLR are known to be pathogenic (PMID: 20809525). Because this variant has also been observed in many individuals with familial hypercholesterolemia, it has been classified as Pathogenic.
U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille RCV000172957 SCV000583658 pathogenic Familial hypercholesterolemia 1 2017-03-30 criteria provided, single submitter clinical testing
Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge RCV000172957 SCV000599325 pathogenic Familial hypercholesterolemia 1 2016-03-01 criteria provided, single submitter curation
GeneDx RCV000599492 SCV000709932 pathogenic not provided 2019-04-10 criteria provided, single submitter clinical testing Not observed in large population cohorts (Lek et al., 2016); Reported as pathogenic or likely pathogenic in ClinVar by other clinical laboratories (ClinVar Variant ID# 189296; Landrum et al., 2016); Canonical splice site variant expected to result in aberrant splicing, although splice outcome is unknown; Deletions involving coding exons in this gene are frequently reported as pathogenic, regardless of frame prediction (Stenson et al., 2014); This variant is associated with the following publications: (PMID: 31447099, 15556092, 21935675, 21475731, 23936638, 14974088, 26036859, 16542394, 16159606, 15199436, 12436241, 11462246, 7616128, 25525159, 22390909)
Color Health, Inc RCV000771312 SCV000903568 pathogenic Familial hypercholesterolemia 2018-08-11 criteria provided, single submitter clinical testing Pathogenic variant based on current evidence: This variant changes a single nucleotide in the intron 3 canonical splice donor site of the LDLR gene and is predicted to cause aberrant splicing. Although RNA studies have not been performed for this variant, other variants affecting the same splice donor site have been shown to cause skipping of exon 3, resulting in an in-frame deletion of part of the ligand binding domain of the LDLR protein (PMID: 27821657). This variant has been reported in numerous individuals affected with familial hypercholesterolemia (PMID: 7616128, 11462246, 14974088, 16542394, 21475731, 28008010). This variant is rare in the general population and has been identified in 0/277264 chromosomes by the Genome Aggregation Database (gnomAD). Based on available evidence, this variant is classified as Pathogenic.
Mendelics RCV000172957 SCV001140980 benign Familial hypercholesterolemia 1 2019-05-28 criteria provided, single submitter clinical testing
Institute of Human Genetics, University of Leipzig Medical Center RCV000172957 SCV001429294 pathogenic Familial hypercholesterolemia 1 2019-05-29 criteria provided, single submitter clinical testing
Brunham Lab, Centre for Heart and Lung Innovation,University of British Columbia RCV000172957 SCV001432645 pathogenic Familial hypercholesterolemia 1 2019-05-10 criteria provided, single submitter research
Baylor Genetics RCV000172957 SCV001521539 pathogenic Familial hypercholesterolemia 1 2020-10-15 criteria provided, single submitter clinical testing This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
CeGaT Praxis fuer Humangenetik Tuebingen RCV000599492 SCV001747204 pathogenic not provided 2021-04-01 criteria provided, single submitter clinical testing
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde,Academisch Medisch Centrum RCV000172957 SCV000606077 pathogenic Familial hypercholesterolemia 1 no assertion criteria provided research

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