ClinVar Miner

Submissions for variant NM_000527.4(LDLR):c.662A>G (p.Asp221Gly) (rs373822756)

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Total submissions: 17
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
LDLR-LOVD, British Heart Foundation RCV000211655 SCV000294862 likely pathogenic Familial hypercholesterolemia 2016-03-25 criteria provided, single submitter literature only
Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge RCV000211655 SCV000322908 pathogenic Familial hypercholesterolemia 2016-03-01 criteria provided, single submitter research 0/190 non-FH alleles; 0/60 healthy control individuals
Robarts Research Institute,Western University RCV000211655 SCV000484733 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 RCV000211655 SCV000503199 likely pathogenic Familial hypercholesterolemia 2016-12-16 criteria provided, single submitter clinical testing subjects mutated among 2600 FH index cases screened = 12 , family members = 7 with co-segregation / FH-Padua / Software predictions: Damaging
Molecular Genetics Laboratory,Centre for Cardiovascular Surgery and Transplantation RCV000211655 SCV000540749 likely pathogenic Familial hypercholesterolemia 2016-11-05 criteria provided, single submitter clinical testing Asp221 bind structural Ca2+.
Invitae RCV000771313 SCV000544638 pathogenic Familial hypercholesterolemias 2018-10-16 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with glycine at codon 221 of the LDLR protein (p.Asp221Gly). The aspartic acid residue is highly conserved and there is a moderate physicochemical difference between aspartic acid and glycine. This variant is clearly defined as a familial hypercholesterolemia causative allele (PMID: 15523646,23375686). It is a common cause of familial hypercholesterolemia in individuals of Italian ancestry, though it has been observed in individuals in many other countries (PMID: 11196104, 15241806, 220236128, 2698793, 25461735). This variant is also known as p.Asp200Gly in the literature. ClinVar contains an entry for this variant (Variation ID: 183092). Experimental studies have shown that this missense change has a deleterious effect on LDLR activity (PMID: 25647241). For these reasons, this variant has been classified as Pathogenic.
U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille RCV000211655 SCV000583715 pathogenic Familial hypercholesterolemia 2017-03-30 criteria provided, single submitter clinical testing
Laboratory of Genetics and Molecular Cardiology,University of São Paulo RCV000211655 SCV000588509 pathogenic Familial hypercholesterolemia 2016-03-01 criteria provided, single submitter research
Fundacion Hipercolesterolemia Familiar RCV000211655 SCV000607481 pathogenic Familial hypercholesterolemia 2016-03-01 criteria provided, single submitter research
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000844743 SCV000711396 pathogenic Familial hypercholesterolemia - homozygous 2019-02-01 criteria provided, single submitter clinical testing proposed classification - variant undergoing re-assessment, contact laboratory
Iberoamerican FH Network RCV000211655 SCV000748133 pathogenic Familial hypercholesterolemia 2016-03-01 criteria provided, single submitter research
Color RCV000771313 SCV000903569 pathogenic Familial hypercholesterolemias 2017-07-26 criteria provided, single submitter clinical testing Pathogenic variant based on current evidence: This variant (also known as p.Asp200Gly in the mature protein and as FH-Padova, FH-Padua) is a missense variant located in the fifth LDLR type A repeat of the ligand binding domain of the LDLR protein. Computational prediction tools and conservation analyses suggest that this variant may have deleterious impact on protein function. Computational splicing tools suggest that this variant may not impact the RNA splicing. An experimental functional study has shown that this variant results in loss of LDLR uptake activity and may be defective for transport through the endoplasmic reticulum (PMID: 21865347). This variant has been identified in more than 100 individuals diagnosed with familial hypercholesterolemia from multiple European ethnicities (PMID: 1301956, 7649546, 9104431, 10208479, 10978268, 17765246, 20145306, 21310417) and is highly recurrent in the Northern Italian population (PMID: 10978268). This variant has been identified in 13/111132 non-Finnish European chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on available evidence, this variant is classified as Pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000771313 SCV000919582 pathogenic Familial hypercholesterolemias 2018-02-16 criteria provided, single submitter clinical testing Variant summary: LDLR c.662A>G (p.Asp221Gly) results in a non-conservative amino acid change located in the Low-density lipoprotein (LDL) receptor class A repeat of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was found in 13/245460 control chromosomes (0.00005296), which does not exceed the maximum expected allele frequency for a pathogenic variant in the LDLR gene (0.0013). The c.662A>G variant has been reported in the literature in numerous individuals affected with Familial Hypercholesterolemia. These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in 10%-<30% of normal LDLR activity (Thormaehlen_2015). Several other variants that cause a change at Asp221 are associated with disease (e.g., D221N, D221Y, and D221V), suggesting the codon is critical for function. Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All of these laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Department of Human Genetics,Laborarztpraxis Dres. Walther, Weindel und Kollegen RCV000211655 SCV000987036 pathogenic Familial hypercholesterolemia 2018-09-25 criteria provided, single submitter clinical testing The mutation occurs at the protein level at position 221 (position 200 of the mature protein) to exchange the amino acid aspartate for glycine. This change has already been described in the literature as the FH Padova-1 allele, detected in patients with familial hypercholesterolemia, and associated with elevated cholesterol and LDL-C levels. It leads to an almost complete loss of LDL receptor activity. We observed this variant in a patient with TC up to 380 mg/dl and LDL-C approx 310 mg/dl. PMID: 25647241, 23375686
Dept. of Genetics and Pharmacogenomics, Merck Research Labs RCV000161962 SCV000189537 not provided not provided no assertion provided in vitro
Cardiovascular Genetics Laboratory,PathWest Laboratory Medicine WA - Fiona Stanley Hospital RCV000211655 SCV000268577 pathogenic Familial hypercholesterolemia 2009-12-12 no assertion criteria provided clinical testing
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde,Academisch Medisch Centrum RCV000211655 SCV000606187 pathogenic Familial hypercholesterolemia no assertion criteria provided research

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