ClinVar Miner

Submissions for variant NM_000527.4(LDLR):c.313+2T>C (rs793888517)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge RCV000172957 SCV000599325 pathogenic Familial hypercholesterolemia 2016-03-01 criteria provided, single submitter curation
Color RCV000771312 SCV000903568 pathogenic Familial hypercholesterolemias 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.
GeneDx RCV000599492 SCV000709932 pathogenic not provided 2018-02-22 criteria provided, single submitter clinical testing The c.313+2 T>C pathogenic variant in the LDLR gene has been reported in multiple individuals of various European ancestry (Lombardi et al., 1995; Nauck et al., 2001; Amsellem et al., 2002; Dedoussis et al., 2004; Graham et al., 2005; Brusgaard et al., 2006; Huijgen et al., 2012). Of note, some genetic testing methods are unable to distinguish between c.313+2 T>C and the c.313+1G>A variant, which is a very common variant identified in the Netherlands (Kusters et al., 2011; Tejedor et al., 2011; Kindt et al., 2013). Additionally, the c.313+2 T>C variant is not observed in large population cohorts (Lek et al., 2016). One recent study identified the c.313+2 T>C variant in one individual with MI/CAD and showed that it did not segregate with disease in two relatives with elevated LDL-C levels and MI/CAD (Brænne et al., 2016). The c.313+2 T>C variant destroys the canonical splice donor site in intron 3 and is predicted to cause abnormal gene splicing. Other splice site variants in the LDLR gene, including two affecting the same canonical splice donor site (c.313+1G>A, c.313+2T>A), have been reported in Human Gene Mutation Database in association with FH (Stenson et al., 2014).
Institute for Integrative and Experimental Genomics,University of Luebeck RCV000172957 SCV000212132 likely benign Familial hypercholesterolemia criteria provided, single submitter research
Invitae RCV000771312 SCV000544667 pathogenic Familial hypercholesterolemias 2018-09-21 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.
LDLR-LOVD, British Heart Foundation RCV000172957 SCV000294609 likely pathogenic Familial hypercholesterolemia 2016-03-25 criteria provided, single submitter literature only
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde,Academisch Medisch Centrum RCV000172957 SCV000606077 pathogenic Familial hypercholesterolemia no assertion criteria provided research
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000844755 SCV000271390 pathogenic Familial hypercholesterolemia - homozygous 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.
Robarts Research Institute,Western University RCV000172957 SCV000484778 likely pathogenic Familial hypercholesterolemia criteria provided, single submitter clinical testing
U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille RCV000172957 SCV000583658 pathogenic Familial hypercholesterolemia 2017-03-30 criteria provided, single submitter clinical testing

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