ClinVar Miner

Submissions for variant NM_000527.5(LDLR):c.313_313+1del (rs875989896)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
LDLR-LOVD, British Heart Foundation RCV000211607 SCV000294601 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 RCV000211607 SCV000503130 pathogenic Familial hypercholesterolemia 1 2016-12-16 criteria provided, single submitter clinical testing subjects mutated among 2600 FH index cases screened = 2 , family members = 2
U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille RCV000211607 SCV000583653 pathogenic Familial hypercholesterolemia 1 2017-03-30 criteria provided, single submitter clinical testing
Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge RCV000211607 SCV000599324 pathogenic Familial hypercholesterolemia 1 2016-03-01 criteria provided, single submitter curation
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease,Montreal Heart Institute RCV000211607 SCV000987703 pathogenic Familial hypercholesterolemia 1 criteria provided, single submitter clinical testing
Cardiovascular Genetics Laboratory,PathWest Laboratory Medicine WA - Fiona Stanley Hospital RCV000211607 SCV000268553 pathogenic Familial hypercholesterolemia 1 2008-07-09 no assertion criteria provided clinical testing
Broad Institute Rare Disease Group, Broad Institute RCV001249011 SCV001422858 likely pathogenic Familial hypercholesterolemia 2020-01-22 no assertion criteria provided curation The c.313_313+1delCG variant in LDLR has been reported in 1 Australian and 1 French individual with familial hypercholesterolemia (PMID: 22883975, 1301956), and was absent from large population studies. This variant has also been reported in ClinVar as pathogenic (Variation ID: 226316). In vitro functional studies provide some evidence that the c.313_313+1delCG variant may slightly impact protein function (PMID: 1301956). However, these types of assays may not accurately represent biological function. This variant occurs in the invariant region (+/- 1/2) of the splice consensus sequence, deletes the last base of the exon inducing a frameshift, and is predicted to cause altered splicing leading to an abnormal or absent protein. Heterozygous loss of function of the LDLR gene is an established disease mechanism in familial hypercholesterolemia. There is an in-frame cryptic splice site within 6 basepairs of the intron-exon boundary that could result in a rescued transcript and may maintain function of LDLR. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PS3_supporting, PS4_supporting, PVS1_moderate, PM2 (Richards 2015).

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