ClinVar Miner

Submissions for variant NM_000527.4(LDLR):c.681C>G (p.Asp227Glu) (rs121908028)

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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
LDLR-LOVD, British Heart Foundation RCV000003876 SCV000294902 likely pathogenic Familial hypercholesterolemia 2016-03-25 criteria provided, single submitter literature only
Robarts Research Institute,Western University RCV000003876 SCV000484734 likely pathogenic Familial hypercholesterolemia criteria provided, single submitter clinical testing
Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies,APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix RCV000003876 SCV000503215 pathogenic Familial hypercholesterolemia 2016-12-16 criteria provided, single submitter clinical testing subjects mutated among 2600 FH index cases screened = 6 , family members = 3 with co-segregation / FH-Afrikaner-1 / Software predictions: Damaging
U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille RCV000003876 SCV000583721 pathogenic Familial hypercholesterolemia 2017-03-30 criteria provided, single submitter clinical testing
Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge RCV000003876 SCV000599342 pathogenic Familial hypercholesterolemia 2016-03-01 criteria provided, single submitter curation
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000844737 SCV000731597 pathogenic Familial hypercholesterolemia - homozygous 2019-02-01 criteria provided, single submitter clinical testing proposed classification - variant undergoing re-assessment, contact laboratory
Iberoamerican FH Network RCV000003876 SCV000748135 pathogenic Familial hypercholesterolemia 2016-03-01 criteria provided, single submitter research
Color RCV000771320 SCV000903585 pathogenic Familial hypercholesterolemias 2018-04-25 criteria provided, single submitter clinical testing Pathogenic variant based on current evidence: This variant (also known as p.Asp206Glu in the mature protein and as FH-Afrikaner-1, FH Maine, FH-1a, and 4D) is a missense variant located in the fifth LDLR type A repeat in the ligand binding domain of the LDLR protein. Computational prediction tools and conservation analyses suggest that this variant may have deleterious impact on the protein function. Computational splicing tools suggest that this variant may not impact the RNA splicing. Experimental functional studies have indicated that the variant may impair LDLR activity (PMID: 1301956, 1463746, 2569482, 3202825, 6324732). This variant is a founder allele in the Afrikaner population and has been shown to segregate with disease in several families (PMID: 11491306, 2352257, 2569482) and has been reported in numerous unrelated individuals affected with familial hypercholesterolemia from multiple ethnicities (PMID: 1952806, 2352257, 2569482, 7718024, 8093663, 9664576, 11491306, 11810272, 15199436, 17087781, 21310417, 23375686, 26892515, 27765764). This variant is rare in the general population and has been identified in 2/244544 chromosomes by the Genome Aggregation Database (gnomAD). Based on available evidence, this variant is classified as Pathogenic.
Invitae RCV000771320 SCV000940292 pathogenic Familial hypercholesterolemias 2018-11-19 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with glutamic acid at codon 227 of the LDLR protein (p.Asp227Glu). The aspartic acid residue is highly conserved and there is a small physicochemical difference between aspartic acid and glutamic acid. This variant is not present in population databases (ExAC no frequency). This variant has been observed in many individuals affected with familial hypercholesterolemia (PMID: 23375686, 27680772, 23669246, 19467224, 21310417, 22883975, 17539906, 21382890) and has been observed as a founder mutation in the Afrikaner population (PMID: 2352257, 2569482). This variant is also known as Asp206Glu and FH Afrikaner-1 in the literature. ClinVar contains an entry for this variant (Variation ID: 3690). Experimental studies have shown that this missense change shows decreased protein processing (PMID: 2569482). For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000003876 SCV000024041 pathogenic Familial hypercholesterolemia 2001-01-01 no assertion criteria provided literature only
Cardiovascular Genetics Laboratory,PathWest Laboratory Medicine WA - Fiona Stanley Hospital RCV000003876 SCV000268580 pathogenic Familial hypercholesterolemia 2008-06-25 no assertion criteria provided clinical testing
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde,Academisch Medisch Centrum RCV000003876 SCV000606198 pathogenic Familial hypercholesterolemia no assertion criteria provided research

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