ClinVar Miner

Submissions for variant NM_000527.5(LDLR):c.269A>G (p.Asp90Gly) (rs771019366)

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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 RCV000211676 SCV000294571 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 RCV000211676 SCV000503123 pathogenic Familial hypercholesterolemia 1 2016-12-16 criteria provided, single submitter clinical testing subjects mutated among 2600 FH index cases screened = 8 , family members = 5 with co-segregation / FH-London-4, 15 to 30% LDLR activity / Software predictions: Damaging
U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille RCV000211676 SCV000583646 pathogenic Familial hypercholesterolemia 1 2017-03-30 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000844733 SCV000732011 likely pathogenic Homozygous familial hypercholesterolemia 2017-10-23 criteria provided, single submitter clinical testing The p.Asp90Gly variant in LDLR has been reported in 5 individuals with familial hypercholesterolemia (FH: 4 in the heterozygous state, 1 in the homozygous state ; Hobbs 1992, Amsellem 2002, Bunn 2002, Do 2015). This variant has also been rep orted in ClinVar (Variation ID# 226313) with one submission (SCV000503124.1) quo ting co-segregation with disease. In vitro functional studies provide some evide nce that the p.Asp90Gly variant may impact protein function (Hobbs 1992). This v ariant has also been identified in 1/66740 European chromosomes by the Exome Agg regation Consortium (ExAC,; dbSNP rs771019366). T his frequency is low enough to be consistent with the frequency of FH in the gen eral population. Computational prediction tools and conservation analysis sugges t that the p.Asp90Gly variant may impact the protein, though this information is not predictive enough to determine pathogenicity. Other missense variants at t his position have been reported in individuals with hypercholesterolemia (HGMD d atabase, Stenson 2017). In summary, although additional studies are required to fully establish its clinical significance, the p.Asp90Gly variant is likely pat hogenic. ACMG/AMP Criteria applied: PM2; PM5_supporting; PP3; PS3_Supporting; PS 4_Supporting (Richards 2015).
Invitae RCV000211676 SCV000823749 pathogenic Familial hypercholesterolemia 1 2018-04-02 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with glycine at codon 90 of the LDLR protein (p.Asp90Gly). The aspartic acid residue is highly conserved and there is a moderate physicochemical difference between aspartic acid and glycine. This variant is present in population databases (rs771019366, ExAC 0.001%). This variant has been reported in individuals affected with autosomal dominant or autosomal recessive familial hypercholesterolemia (PMID: 1301956, 12436241, 11857755, 9026534, 12436241, 9259195, 19837725). This variant is also known as p.Asp69Gly in the literature. ClinVar contains an entry for this variant (Variation ID: 226313). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). Two different missense substitutions at this codon (p.Asp90Asn and p.Asp90Glu) have been determined to be pathogenic (PMID: 25962062, 21376320, 27765764, 15823276, 16343504, 12837857, 27824480, 20809525). Other missense substitutions at this codon (p.Asp90Ala and p.Asp90Tyr) have been reported in individuals affected with familial hypercholesterolemia (PMID: 19026292, 8347689). This suggests that the aspartic acid residue is critical for LDLR protein function and that other missense substitutions at this position may also be pathogenic. For these reasons, this variant has been classified as Pathogenic.
Cardiovascular Genetics Laboratory,PathWest Laboratory Medicine WA - Fiona Stanley Hospital RCV000211676 SCV000268549 pathogenic Familial hypercholesterolemia 1 2008-06-05 no assertion criteria provided clinical testing
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde,Academisch Medisch Centrum RCV000211676 SCV000606058 pathogenic Familial hypercholesterolemia 1 no assertion criteria provided research

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