ClinVar Miner

Submissions for variant NM_000527.4(LDLR):c.1358+2T>A (rs193922567)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Integrated Genetics/Laboratory Corporation of America RCV000030127 SCV000052782 pathogenic Familial hypercholesterolemia 1 2011-08-18 criteria provided, single submitter curation Converted during submission to Pathogenic.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000844727 SCV000271382 pathogenic Familial hypercholesterolemia - homozygous 2015-12-21 criteria provided, single submitter clinical testing The c.1358+2T>A variant in LDLR has been reported in at least 2 individuals with familial hypercholesterolemia and segregated with disease in both families (Wei ss 2000, Nauck 2001). This variant has also been identified in 1/66288 European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitut e.org; dbSNP rs193922567) and is reported in ClinVar (Varition ID: 36455) . Howe ver, this frequency is low enough to be consistent with the frequency of familia l hypercholesterolemia in the general population. This variant occurs in the inv ariant region (+/- 1,2) of the splice consensus sequence and is predicted to cau se altered splicing leading to an abnormal or absent protein. Heterozygous loss of function in LDLR is an established disease mechanism in individuals with fami lial hypercholesterolemia. In summary, this variant meets criteria to be classif ied as pathogenic for familial hypercholesterolemia in an autosomal dominant man ner based upon the predicted impact to the protein and observation in affected i ndividuals. ACMG/AMP criteria applied: PVS1, PM2, PS4_Supporting.
LDLR-LOVD, British Heart Foundation RCV000030127 SCV000295384 likely pathogenic Familial hypercholesterolemia 1 2016-03-25 criteria provided, single submitter literature only
Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies,APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix RCV000030127 SCV000503340 pathogenic Familial hypercholesterolemia 1 2016-12-16 criteria provided, single submitter clinical testing subject mutated among 2600 FH index cases screened = 1
Molecular Genetics Laboratory,Centre for Cardiovascular Surgery and Transplantation RCV000030127 SCV000540812 pathogenic Familial hypercholesterolemia 1 2016-11-05 criteria provided, single submitter clinical testing
Invitae RCV000775065 SCV000544652 pathogenic Familial hypercholesterolemia 2018-12-18 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 9 of the LDLR gene. It is expected to disrupt mRNA splicing and likely results in an absent or disrupted protein product. Loss-of-function variants in LDLR are known to be pathogenic. This particular variant has been reported in the literature (PMID: 11196104, 11462246, 12124988, 21310417). ClinVar contains an entry for this variant (Variation ID: 36455). For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV000520751 SCV000617509 pathogenic not provided 2018-04-09 criteria provided, single submitter clinical testing The c.1358+2 T>A pathogenic variant in the LDLR gene variant has been reported in several unrealted individuals from different ethnic backgrounds with FH (Weiss et al., 2000; Nauck et al., 2001; Fouchier et al., 2005; Duskova et al., 2011; Tichy et al., 2012; Hooper et al., 2012). Additionally, the c.1358+2 T>A variant has been classified as pathogenic by several other clinical laboratories in ClinVar (SCV000271382.2, SCV000503340.1, SCV000540812.1, SCV000544652.2, SCV000052782.1; Landrum et al., 2016). Furthermore, this variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). The c.1358+2 T>A variant destroys the canonical splice donor site in intron 9 and is predicted to cause abnormal gene splicing. In addition, other splice site variants in the LDLR gene have been reported in the Human Gene Mutation Database in association with FH (Stenson et al., 2014).
Color RCV000775065 SCV000909166 pathogenic Familial hypercholesterolemia 2018-09-14 criteria provided, single submitter clinical testing Pathogenic variant based on current evidence: This variant changes a single nucleotide in intron 9 canonical splice donor site of the LDLR gene. This variant is predicted to cause aberrant splicing and likely results in an absent or disrupted protein product. To our knowledge, RNA studies have not been performed for this variant. While this variant is rare in the general population (1/245944 chromosomes in the Genome Aggregation Database (gnomAD)), this variant has been reported in over 10 individuals affected with familial hypercholesterolemia (PMID: 11196104, 11462246, 21310417, 22883975, 22698793, 28008010). Based on available evidence, this variant is classified as Pathogenic.
Cardiovascular Genetics Laboratory,PathWest Laboratory Medicine WA - Fiona Stanley Hospital RCV000030127 SCV000268612 pathogenic Familial hypercholesterolemia 1 2008-06-05 no assertion criteria provided clinical testing
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde,Academisch Medisch Centrum RCV000030127 SCV000606405 pathogenic Familial hypercholesterolemia 1 no assertion criteria provided research

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