Submissions for variant NM_000527.5(LDLR):c.662A>G (p.Asp221Gly)

Total submissions: 21

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
LDLR-LOVD, British Heart Foundation	RCV000211655	SCV000294862	likely pathogenic	Familial hypercholesterolemia 1	2016-03-25	criteria provided, single submitter	literature only
Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge	RCV000211655	SCV000322908	pathogenic	Familial hypercholesterolemia 1	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 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	RCV000211655	SCV000503199	likely pathogenic	Familial hypercholesterolemia 1	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 1	2016-11-05	criteria provided, single submitter	clinical testing	Asp221 bind structural Ca2+.
Invitae	RCV000771313	SCV000544638	pathogenic	Familial hypercholesterolemia	2019-11-29	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 1	2017-03-30	criteria provided, single submitter	clinical testing
Laboratory of Genetics and Molecular Cardiology, University of São Paulo	RCV000211655	SCV000588509	pathogenic	Familial hypercholesterolemia 1	2016-03-01	criteria provided, single submitter	research
Fundacion Hipercolesterolemia Familiar	RCV000211655	SCV000607481	pathogenic	Familial hypercholesterolemia 1	2016-03-01	criteria provided, single submitter	research
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine	RCV000844743	SCV000711396	pathogenic	Homozygous familial hypercholesterolemia	2019-03-03	criteria provided, single submitter	clinical testing	The p.Asp221Gly variant in LDLR has been reported in >75 individuals with familial hypercholesterolemia (FH), including in 4 homozygotes who presented with more severe disease (Hobbs 1992, Chmara 2010, Bertolini 2013). However, not all individuals carrying this variant presented with high cholesterol levels (Bertolini 2013, Thormaehlen 2015). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID 183092) and has been identified in 13/111132 European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs373822756). Please note that this frequency is low enough to be consistent with the frequency of FH in the general population. In vitro functional studies provide some evidence that the p.Asp221Gly variant may impact protein function (Thormaehlen 2015). In summary, this variant meets criteria to be classified as pathogenic for familial hypercholesterolemia in an autosomal dominant manner based upon presence in affected individuals, low frequency in the general population, computational and functional evidence. The ACMG/AMP Criteria applied: PS4, PM3_Strong, PP3, PS3_Supporting.
Iberoamerican FH Network	RCV000211655	SCV000748133	pathogenic	Familial hypercholesterolemia 1	2016-03-01	criteria provided, single submitter	research
Color	RCV000771313	SCV000903569	pathogenic	Familial hypercholesterolemia	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 hypercholesterolemia	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 1	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
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000161962	SCV001134266	pathogenic	not provided	2019-03-21	criteria provided, single submitter	clinical testing	The best available variant frequency is uninformative. Found in at least one symptomatic patient. Predicted to have a damaging effect on the protein. Assessment of experimental evidence suggests this variant results in abnormal protein function. Occurs in multiple cases with a recessive pathogenic variant in the same gene.
CeGaT Praxis fuer Humangenetik Tuebingen	RCV000161962	SCV001246005	pathogenic	not provided	2020-02-01	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Leipzig Medical Center	RCV000211655	SCV001429303	pathogenic	Familial hypercholesterolemia 1	2019-03-18	criteria provided, single submitter	clinical testing
Brunham Lab, Centre for Heart and Lung Innovation,University of British Columbia	RCV000211655	SCV001432569	pathogenic	Familial hypercholesterolemia 1	2019-06-04	criteria provided, single submitter	research
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 1	2009-12-12	no assertion criteria provided	clinical testing
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde,Academisch Medisch Centrum	RCV000211655	SCV000606187	pathogenic	Familial hypercholesterolemia 1		no assertion criteria provided	research