ClinVar Miner

Submissions for variant NM_000527.5(LDLR):c.313+1G>C (rs112029328)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000844754 SCV000271389 pathogenic Homozygous familial hypercholesterolemia 2019-06-07 criteria provided, single submitter clinical testing The c.313+1G>C variant in LDLR has been identified in >80 Spanish individuals with familial hypercholesterolemia (FH; Tejedor 2011). It has also been identified in 1/113710 European chromosomes by gnomAD (https://gnomad.broadinstitute.org). This variant occurs in the invariant region (+/- 1,2) of the splice consensus sequence and is predicted to cause altered splicing leading to an abnormal or absent protein. Heterozygous loss of LDLR function is an established disease mechanism in FH. In summary, this variant meets our criteria to be classified as pathogenic for FH in an autosomal dominant manner. PVS1_Strong, PS4, PM2.
LDLR-LOVD, British Heart Foundation RCV000213674 SCV000294605 likely pathogenic Familial hypercholesterolemia 1 2016-03-25 criteria provided, single submitter literature only
Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge RCV000213674 SCV000322889 pathogenic Familial hypercholesterolemia 1 2016-03-01 criteria provided, single submitter research 0/208 non-FH alleles; 0/32 normolipidemic individuals; 0/60 healthy control individuals
Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies,APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix RCV000213674 SCV000503134 pathogenic Familial hypercholesterolemia 1 2016-12-16 criteria provided, single submitter clinical testing subject mutated among 2600 FH index cases screened = 1
Fundacion Hipercolesterolemia Familiar RCV000213674 SCV000607444 pathogenic Familial hypercholesterolemia 1 2016-03-01 criteria provided, single submitter research
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde,Academisch Medisch Centrum RCV000213674 SCV000606075 pathogenic Familial hypercholesterolemia 1 no assertion criteria provided research
Iberoamerican FH Network RCV000213674 SCV000748173 pathogenic Familial hypercholesterolemia 1 2016-03-01 no assertion criteria provided research
Broad Institute Rare Disease Group,Broad Institute RCV001249083 SCV001423040 uncertain significance Familial hypercholesterolemia 2020-01-22 no assertion criteria provided curation The c.313+1G>C variant in LDLR has been reported in at least 5 Spanish and/or Dutch individuals with familial hypercholesterolemia (PMID: 21935675, 7616128, 10790219), and has been identified in 0.0009% (1/113710) of European non-Finnish chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs112029328). This variant has also been reported in ClinVar as both pathogenic and likely pathogenic (Variation ID: 228358). This variant occurs in the invariant region (+/- 1/2) of the splice consensus sequence and is predicted to cause altered splicing leading to an abnormal or absent protein. 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. Heterozygous loss of function of the LDLR gene is an established disease mechanism in familial hypercholesterolemia. In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PVS1_moderate, PS4_supporting (Richards 2015).

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