ClinVar Miner

Submissions for variant NM_000527.4(LDLR):c.1474G>A (p.Asp492Asn) (rs373646964)

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Total submissions: 15
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
LDLR-LOVD, British Heart Foundation RCV000237459 SCV000295458 likely pathogenic Familial hypercholesterolemia 1 2016-03-25 criteria provided, single submitter literature only
Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge RCV000237459 SCV000322957 uncertain significance Familial hypercholesterolemia 1 2016-03-01 criteria provided, single submitter research 0/184 non-FH alleles; 0/100 healthy control individuals
Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies,APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix RCV000237459 SCV000503353 likely pathogenic Familial hypercholesterolemia 1 2016-12-16 criteria provided, single submitter clinical testing subjects mutated among 2600 FH index cases screened = 10 , family members = 5 with unclear co-segregation / previously described in association with FH/Software predictions: Conflicting
Molecular Genetics Laboratory,Centre for Cardiovascular Surgery and Transplantation RCV000237459 SCV000540820 likely pathogenic Familial hypercholesterolemia 1 2016-11-05 criteria provided, single submitter clinical testing
U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille RCV000237459 SCV000583835 pathogenic Familial hypercholesterolemia 1 2017-03-30 criteria provided, single submitter clinical testing
Laboratory of Genetics and Molecular Cardiology, University of São Paulo RCV000237459 SCV000588582 uncertain significance Familial hypercholesterolemia 1 2016-03-01 criteria provided, single submitter research
Fundacion Hipercolesterolemia Familiar RCV000237459 SCV000607602 uncertain significance Familial hypercholesterolemia 1 2016-03-01 criteria provided, single submitter research
Integrated Genetics/Laboratory Corporation of America RCV000590270 SCV000697197 pathogenic Familial hypercholesterolemia 2017-06-05 criteria provided, single submitter clinical testing Variant summary: The LDLR c.1474G>A (p.Asp492Asn) variant involves the alteration of a conserved nucleotide. 4/5 in silico tools predict a damaging outcome for this variant. This variant was found in 2/121480 control chromosomes at a frequency of 0.0000165, which does not exceed the estimated maximal expected allele frequency of a pathogenic LDLR variant (0.0012508). This variant has been reported in multiple affected FH patients including heterozygous patients and compound heterozygous patients (Mak_1998, Chiou_2010, Bertolini_2013, Blaha_2015). Variant was shown to segregate with disease in at least one of the reported families (Blaha_2015). Variants involving nearby nucleotides such as c.1474G>C, c.1474delG, c.1475A>G, etc, have been reported in affected individuals suggesting variant of interest is located in a mutiaotn hotspot. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as likely pathogenic. Taken together, this variant is classified as pathogenic.
Robarts Research Institute,Western University RCV000237459 SCV000782916 uncertain significance Familial hypercholesterolemia 1 2018-01-02 criteria provided, single submitter clinical testing
Human Genome Sequencing Center Clinical Lab,Baylor College of Medicine RCV000237459 SCV000839982 likely pathogenic Familial hypercholesterolemia 1 2017-04-26 criteria provided, single submitter clinical testing This c.1474G>A (p.Asp492Asn) variant has been reported in a 42 year old male patient with familial hypercholesterolemia from a cohort of 30 patients [reported as D471N, FH Graz-1 in PMID 9763532]. This variant was also reported in a patient presenting with a total cholesterol level of 23 mmol/L and xanthomas [PMID 25936317]; this patient also carried a second allele (p.Gly592Glu), which is classified as pathogenic by our laboratory . This variant was further detected in a patient from a cohort of 2,078 patients from Italy [PMID 23375686]; this patient also carried a p.Cys698Trp variant, classified as a variant of unknown significance by our laboratory at this time. Additional variants affecting the same amino acid at position 492 (p.Asp492Gly and p.Asp492His) have been reported in patients with familial hypercholesterolemia [PMID 16250003, 10208479].This variant was reported in 2 heterozygous individuals in the ExAC database (http://exac.broadinstitute.org/variant/19-11224326-G-A). Asparagine at amino acid position 492 of the LDLR protein is highly conserved in mammals. While not validated for clinical use, the computer-based algorithms predict this p.Asp492Asn change to be deleterious. This variant is thus classified as likely pathogenic.
Color RCV000590270 SCV000903572 likely pathogenic Familial hypercholesterolemia 2018-09-11 criteria provided, single submitter clinical testing Likely Pathogenic variant based on current evidence: This missense variant (also known as p.Asp471Asn in the mature protein) is located in the third LDLR type B repeat of the EGF precursor homology domain of the LDLR protein. Computational prediction tools and conservation analyses suggest that this variant may have deleterious impact on the protein function. However, an experimental study has shown that the mutant LDLR retains LDL uptake ability (PMID: 25647241). Computational splicing tools suggest that this variant may not impact the RNA splicing. This variant has been reported in over 15 individuals affected with familial hypercholesterolemia (PMID: 11737238, 12436241, 15199436, 15823288, 17539906, 19318025, 19446849, 20538126, 21310417, 22698793, 9763532). It has also been shown to segregate with disease in a Hong Kong Chinese family (Faiz 2014). The variant has been identified in 6/246236 chromosomes in the general population by the Genome Aggregation Database (gnomAD). although additional studies are required to fully establish its clinical significance, this variant is classified as Likely Pathogenic based on available evidence.
Invitae RCV000590270 SCV000939301 pathogenic Familial hypercholesterolemia 2018-11-21 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with asparagine at codon 492 of the LDLR protein (p.Asp492Asn). The aspartic acid residue is highly conserved and there is a small physicochemical difference between aspartic acid and asparagine. This variant is present in population databases (rs373646964, ExAC 0.003%). This variant has been observed to segregate with familial hypercholesterolemia in a family (PMID: 10230472). This variant has also been observed in several individuals with myocardial infarction (PMID: 25647241, 25487149) and many individuals with familial hypercholesterolemia (PMID: 9763532, 25936317, 20236128, 11005141, 23375686, 27680772, 22698793). This variant is also known as Asp471Asn and Graz-1. ClinVar contains an entry for this variant (Variation ID: 161285). A single experimental study showed that this missense change did not disrupt LDL uptake, but this has not been confirmed in additional studies (PMID: 25647241). This variant disrupts the p.Asp492 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been observed in individuals with LDLR-related disease (PMID: 16250003, 10208479), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
Dept. of Genetics and Pharmacogenomics, Merck Research Labs RCV000161989 SCV000189564 not provided not provided no assertion provided in vitro
CSER _CC_NCGL, University of Washington RCV000148592 SCV000190307 uncertain significance Hypercholesterolaemia 2014-06-01 no assertion criteria provided research
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde,Academisch Medisch Centrum RCV000237459 SCV000606438 pathogenic Familial hypercholesterolemia 1 no assertion criteria provided research

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