Total submissions: 23
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
LDLR- |
RCV000211655 | SCV000294862 | likely pathogenic | Familial hypercholesterolemia 1 | 2016-03-25 | criteria provided, single submitter | literature only | |
Cardiovascular Research Group, |
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, |
RCV000211655 | SCV000484733 | likely pathogenic | Familial hypercholesterolemia 1 | criteria provided, single submitter | clinical testing | ||
Centre de Génétique Moléculaire et Chromosomique, |
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, |
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 - |
RCV000211655 | SCV000583715 | pathogenic | Familial hypercholesterolemia 1 | 2017-03-30 | criteria provided, single submitter | clinical testing | |
Laboratory of Genetics and Molecular Cardiology, |
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, |
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 Health, |
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, |
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. |
Ce |
RCV000161962 | SCV001246005 | pathogenic | not provided | 2020-02-01 | criteria provided, single submitter | clinical testing | |
Institute of Human Genetics, |
RCV000211655 | SCV001429303 | pathogenic | Familial hypercholesterolemia 1 | 2019-03-18 | criteria provided, single submitter | clinical testing | |
Brunham Lab, |
RCV000211655 | SCV001432569 | pathogenic | Familial hypercholesterolemia 1 | 2019-06-04 | criteria provided, single submitter | research | |
Human Genome Sequencing Center Clinical Lab, |
RCV000771313 | SCV001435007 | pathogenic | Familial hypercholesterolemia | 2019-03-01 | criteria provided, single submitter | clinical testing | The c.662A>G (p.Asp221Gly) variant in the LDLR gene has been reported in multiple unrelated individuals affected with familial hypercholesterolemia (PMID 1301956, 11196104, 15241806, 20145306,23375686) and has also been reported in multiple myocardial infarction cases while absent from healthy controls (PMID 25487149). Independent functional studies demonstrated deleterious effect of the p.Asp221Gly variant (PMID 1301956, 25647241). Multiple algorithms predicted this change to be damaging. Therefore, this c.662A>G (p.Asp221Gly) variant in the LDLR gene is classified as pathogenic. |
Dept. |
RCV000161962 | SCV000189537 | not provided | not provided | no assertion provided | in vitro | ||
Cardiovascular Genetics Laboratory, |
RCV000211655 | SCV000268577 | pathogenic | Familial hypercholesterolemia 1 | 2009-12-12 | no assertion criteria provided | clinical testing | |
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, |
RCV000211655 | SCV000606187 | pathogenic | Familial hypercholesterolemia 1 | no assertion criteria provided | research | ||
Natera, |
RCV000771313 | SCV001456147 | pathogenic | Familial hypercholesterolemia | 2020-09-16 | no assertion criteria provided | clinical testing |