ClinVar Miner

Submissions for variant NM_000527.4(LDLR):c.682G>T (p.Glu228Ter) (rs121908029)

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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 RCV000211631 SCV000294907 pathogenic Familial hypercholesterolemia 1 2016-03-25 criteria provided, single submitter literature only
Robarts Research Institute,Western University RCV000211631 SCV000484711 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 RCV000211631 SCV000503219 pathogenic Familial hypercholesterolemia 1 2016-12-16 criteria provided, single submitter clinical testing subjects mutated among 2600 FH index cases screened = 7 , family member = 1 with co-segregation / FH-Morocco, 2% LDLR Activity
U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille RCV000211631 SCV000583726 pathogenic Familial hypercholesterolemia 1 2017-03-30 criteria provided, single submitter clinical testing
Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge RCV000211631 SCV000599343 pathogenic Familial hypercholesterolemia 1 2016-03-01 criteria provided, single submitter curation
Athena Diagnostics Inc RCV000518828 SCV000614010 pathogenic not provided 2013-06-27 criteria provided, single submitter clinical testing
Invitae RCV000589867 SCV000627046 pathogenic Familial hypercholesterolemia 2018-12-27 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Glu228*) in the LDLR gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs121908029, ExAC 0.01%). This variant has been reported in multiple unrelated individuals and affected with familial hypercholesterolemia (PMID: 1301956, 11462246, 15359125, 19843101, 21310417, 23054246). This variant is also known as p.Glu207* in the literature. ClinVar contains an entry for this variant (Variation ID: 226333). Loss-of-function variants in LDLR are known to be pathogenic (PMID: 20809525). For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV000518828 SCV000680545 pathogenic not provided 2018-10-01 criteria provided, single submitter clinical testing E228X (referred to as Stop207 and FH Morocco) has been reported previously as a novel variant in one individual of Moroccan American ancestry with primary hypercholesterolemia who was homozygous for E228X (Hobbs et al., 1992). E228X is predicted to cause loss of normal protein function either by protein truncation or nonsense-mediated mRNA decay. Furthermore, this particular area of the LDLR gene appears to be a mutation hotspot, and other nonsense variants in the LDLR gene have been reported in Human Gene Mutation Database in association with FH (Stenson et al., 2014). Furthermore, the E228X variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; Exome Variant Server).In summary, E228X in the LDLR gene is interpreted as a pathogenic variant.
Integrated Genetics/Laboratory Corporation of America RCV000589867 SCV000697248 pathogenic Familial hypercholesterolemia 2016-11-21 criteria provided, single submitter clinical testing Variant summary: The LDLR c.682G>T (p.Glu228X) variant (alternatively also known as E207X) results in a premature termination codon, predicted to cause a truncated or absent LDLR protein due to nonsense mediated decay (NMD), which are commonly known mechanisms for disease. Functional analyses show that this variant results into NMD causing absent LDLR protein (Charng_2006) and/or extremely low LDL receptor activity (Hobbs_1992). Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g. p.Cys276X, p.Val295fsX75). This variant is widely reported in FH patients and is a recurrent pathogenic mutation (Hobbs_1992, Leren_2004, Muller_2004, Charng_2006, Humphries_2006). This variant was found in 2/117006 control chromosomes at a frequency of 0.0000171, which does not exceed the estimated maximal expected allele frequency of a pathogenic LDLR variant (0.0025031). The heterozygotes in ExAC are likely to represent as subclinical cases or reduced penetrance. Multiple clinical lab/research centers have classified this variant as pathogenic. Taken together, this variant is classified as Pathogenic.
Fulgent Genetics,Fulgent Genetics RCV000211631 SCV000894171 pathogenic Familial hypercholesterolemia 1 2018-10-31 criteria provided, single submitter clinical testing
Color RCV000589867 SCV000903587 pathogenic Familial hypercholesterolemia 2017-07-24 criteria provided, single submitter clinical testing Pathogenic variant based on current evidence: This variant (also known as p.Glu207* in the mature protein and as FH Morocco) changes a single nucleotide in exon 4 of the LDLR gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. To our knowledge, functional assays have not been performed for this variant nor has this variant been reported in individuals affected with familial hypercholesterolemia in the literature. While this variant is rare in the general population (3/275344 chromosomes by the Genome Aggregation Database (gnomAD)), this variant has been reported in over 15 individuals and affected with familial hypercholesterolemia (PMID: 1301956, 11462246, 15359125, 23054246, 28008010). Loss-of-function truncation variants in the LDLR gene are known to be pathogenic (PMID: 20809525). Based on available evidence, this variant is classified as Pathogenic.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000825617 SCV000966969 pathogenic Familial hypercholesterolemia - homozygous 2018-03-09 criteria provided, single submitter clinical testing The p.Glu228X variant in LDLR (also described as p.Glu207X in the literature) ha s been reported in 23 individuals with familial hypercholesterolemia (FH; Hobbs 1992, Nauck 2001, Bodamer 2002, Kim 2004, Taylor 2007, Hola 2009, Vandrovcova 20 13, Han 2015, Du 2016, Abul-Husn 2016) and segregated with disease in 6 affected relatives from 3 families (Bodamer 2002, Kim 2004). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID 226333). In vi tro functional studies provide some evidence that the p.Glu228X variant may impa ct protein function (Hobbs 1992, Holla 2009). This variant has also been identif ied in 1/23818 African and 2/125438 European chromosomes by the Genome Aggregati on Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs12190829). This f requency is low enough to be consistent with the frequency of FH in the general population. This nonsense variant leads to a premature termination codon at posi tion 228, which is predicted to lead to a truncated or absent protein. Heterozyg ous loss of function of the LDLR gene is an established disease mechanism in ind ividuals with FH. In summary, this variant meets criteria to be classified as pa thogenic for FH in an autosomal dominant manner based upon presence in multiple affected individuals, segregation studies, low frequency in the general populati on, predicted impact on the protein, and functional evidence. ACMG/AMP criteria applied (Richards 2015): PVS1; PM2; PS4; PP1_Moderate; PS3_Supporting.
Department of Human Genetics,Laborarztpraxis Dres. Walther, Weindel und Kollegen RCV000211631 SCV000987035 pathogenic Familial hypercholesterolemia 1 2018-10-09 criteria provided, single submitter clinical testing The mutation leads to a premature stop codon at protein level at position 228 (position 207 of the mature protein). This change has already been described in the literature as FH Morocco allele and is associated with elevated cholesterol and LDL-C levels. PMID: 1131376, 7649546, 7903864
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology RCV000211631 SCV000993423 pathogenic Familial hypercholesterolemia 1 2019-03-20 criteria provided, single submitter research
Cardiovascular Genetics Laboratory,PathWest Laboratory Medicine WA - Fiona Stanley Hospital RCV000211631 SCV000268582 pathogenic Familial hypercholesterolemia 1 2011-08-11 no assertion criteria provided clinical testing
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde,Academisch Medisch Centrum RCV000211631 SCV000606203 pathogenic Familial hypercholesterolemia 1 no assertion criteria provided research
Stanford Center for Inherited Cardiovascular Disease, Stanford University RCV000518828 SCV000925136 pathogenic not provided 2017-11-16 no assertion criteria provided provider interpretation p.Glu228* (c.682G>T) in exon 4 of the LDLR gene (NM_000527.4; chr19-11216264-G-T) SCICD Classification: pathogenic variant based on strong case data. We do feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). Gene-level evidence: LDLR: LDL receptors are located on the surface of the liver and play an important role in LDL recycling. Pathogenic variants in LDLR account for 80% of cases of familial hypercholesterolemia. Both missense and truncating/frameshift variants can be pathogenic. Truncating variants in LDLR are a known mechanism of disease (Marduel et al 2010). Exon 4 in LDLR encodes a binding domain for both apoB and apoE. Case data (not including our patient): at least 12. ClinVar: LDLR-LOVD, British Heart Foundation, University of Western Ontario, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix (7 unrelated cases and segregated with disease in 1 family member), Lille University, Cardiovascular Research Group, Istituto Nacional de Saude Doutor Ricardo Jorge, Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde,Academisch Medisch Centrum, Cardiovascular Genetics Laboratory,PathWest Laboratory Medicine WA - Fiona Stanley Hospital - all likely pathogenic or pathogenic. Cases in the literature: At least 12. Note: this variant is also known as p.Glu207* in the literature. Hobbs et al 1992: this variant caused less than 2% LDLR activity. The patient was Moroccan American. Nauck et al 2001: This variant was found in 5 patients with FH. Kim et al 2004: Found in 2 of 25 unrelated Korean patients with FH. Taylor et al 2010: Detected this variant in 1 of 20 patients with definite FH. Dušková et al 2011: detected in 1 of 1945 unrelated Czech patients with FH. Futema et al 2012: 2 of 48 patients with FH (British descent). Segregation data: none reported Functional data: Truncating variants in LDLR are a known mechanism of disease (Marduel et al 2010). Exon 4 in LDLR encodes a binding domain for both apoB and apoE (Hobbs et al 1992). Conservation data: The glutamic acid at codon 228 is completely conserved across species. Amino acid at position 227 is also completely conserved. Nearby pathogenic variants at this codon or neighboring codons: Many nearby truncating variants near this codon. Population data: Highest MAF in African population: 0.0066%. The variant was reported online in 2 of 122,195 individuals in the Genome Aggregation Consortium Dataset (gnomAD; http://gnomad.broadinstitute.org/), which currently includes variant calls on >140,000 unrelated individuals of African, Asian, European, Ashkenazi, Latino descent. Specifically, the variant was observed in 1 of 7,543 individuals of African descent (MAF=0.0066%) and 1 of 55,223 individuals of European descent. The phenotype of those individuals is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease. Note that other variants with strong evidence for pathogenicity have been seen at similar frequencies in datasets like this so this does not necessarily rule out pathogenicity (Pan et al 2012).

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