ClinVar Miner

Submissions for variant NM_000527.5(LDLR):c.681C>G (p.Asp227Glu) (rs121908028)

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Total submissions: 15
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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 1 2016-03-25 criteria provided, single submitter literature only
Robarts Research Institute,Western University RCV000003876 SCV000484734 likely pathogenic Familial hypercholesterolemia 1 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 1 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 1 2017-03-30 criteria provided, single submitter clinical testing
Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge RCV000003876 SCV000599342 pathogenic Familial hypercholesterolemia 1 2016-03-01 criteria provided, single submitter curation
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000844737 SCV000731597 pathogenic Homozygous familial hypercholesterolemia 2019-03-03 criteria provided, single submitter clinical testing The p.Asp227Glu variant in LDLR (also known as the FH Afrikaner 1 allele) is a founder variant in the Afrikan population and is thought to account for 65 - 75% of familial hypercholesterolemia in Afrikans (Leitersdorf 1989, Kotze 1990, Kotze 1994). This variant has also been identified in at least 7 Caucasian individuals with familial hypercholesterolemia (Gudnason 1993, Callis 1998, Fouchier 2001, Bertolini 2013, Sharifi 2016) and has been reported in ClinVar (Variation ID 3690). Additionally, in vitro functional studies provide some evidence that the p.Asp227Glu variant may impair receptor activity (Fourie 1988). This variant has been identified in 1/33548 Latino chromosomes by the Genome Aggregation Database (gnomAD; http://gnomad.broadinstitute.org; dbSNP rs121908028). This frequency is low enough to be consistent with the frequency of familial hypercholesterolemia (FH) in the general population. In summary, this variant meets criteria to be classified as pathogenic for FH in an autosomal dominant manner based upon low frequency in controls, functional evidence, and presence in multiple affected individuals. The ACMG/AMP Criteria applied: PS4, PP1_Strong, PM2, PP3, PS3_Supporting.
Iberoamerican FH Network RCV000003876 SCV000748135 pathogenic Familial hypercholesterolemia 1 2016-03-01 criteria provided, single submitter research
Color RCV000771320 SCV000903585 pathogenic Familial hypercholesterolemia 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 hypercholesterolemia 2019-11-01 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.
Integrated Genetics/Laboratory Corporation of America RCV000771320 SCV001361870 pathogenic Familial hypercholesterolemia 2019-07-15 criteria provided, single submitter clinical testing Variant summary: LDLR c.681C>G (p.Asp227Glu) results in a conservative amino acid change located in the fifth class A repeat domain (IPR002172) of the LDL receptor protein. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8.1e-06 in 248142 control chromosomes (gnomAD). c.681C>G has been reported in the literature (in heterozygous-, homozygous- or compound heterozygous state) in numerous individuals affected with Familial Hypercholesterolemia (e.g. Kotze_1990, Gudnason_1994, Bertolini_2013, Sharifi_2016, Thedrez_2018). These data indicate that the variant is very likely to be associated with disease. Publications also reported experimental evidence evaluating an impact on protein function, demonstrating slower processing and decreased cell surface expression for the variant protein (e.g. Leitersdorf_1989, Thedrez_2018). Seven submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as pathogenic (6x) or likely pathogenic (1x). Based on the evidence outlined above, the variant was classified as pathogenic.
Brunham Lab, Centre for Heart and Lung Innovation,University of British Columbia RCV000003876 SCV001432571 pathogenic Familial hypercholesterolemia 1 2019-06-05 criteria provided, single submitter research
OMIM RCV000003876 SCV000024041 pathogenic Familial hypercholesterolemia 1 2001-01-01 no assertion criteria provided literature only
Cardiovascular Genetics Laboratory,PathWest Laboratory Medicine WA - Fiona Stanley Hospital RCV000003876 SCV000268580 pathogenic Familial hypercholesterolemia 1 2008-06-25 no assertion criteria provided clinical testing
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde,Academisch Medisch Centrum RCV000003876 SCV000606198 pathogenic Familial hypercholesterolemia 1 no assertion criteria provided research
Biochemical Molecular Genetic Laboratory,King Abdulaziz Medical City RCV000003876 SCV001190761 likely pathogenic Familial hypercholesterolemia 1 2020-02-05 no assertion criteria provided clinical testing

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