ClinVar Miner

Submissions for variant NM_000527.5(LDLR):c.1502C>T (p.Ala501Val) (rs755667663)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
LDLR-LOVD, British Heart Foundation RCV000238372 SCV000295471 likely pathogenic Familial hypercholesterolemia 1 2016-03-25 criteria provided, single submitter literature only
U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille RCV000238372 SCV000583839 pathogenic Familial hypercholesterolemia 1 2017-03-30 criteria provided, single submitter clinical testing
GeneDx RCV000519148 SCV000617511 likely pathogenic not provided 2017-08-30 criteria provided, single submitter clinical testing The A501V variant in the LDLR gene has been reported previously in two unrelated individuals with familial hypercholesterolemia and in an individual with early onset myocardial infarction (Damgaard et al., 2005; Bertolini et al., 2013; Do et al., 2015). The A501V variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The A501V variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Missense variants in the same (A501E) nearby residues (G496D, T497P, V498F, S499P, D502Y, K504E, G505D, V506M) have been reported in the Human Gene Mutation Database in association with familial hypercholesterolemia (Stenson et al., 2014), supporting the functional importance of this region of the protein. We interpret A501V as a likely pathogenic variant.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000770762 SCV000697199 likely pathogenic Familial hypercholesterolemia 2019-02-28 criteria provided, single submitter clinical testing Variant summary: LDLR c.1502C>T (p.Ala501Val) results in a non-conservative amino acid change located in the LDLR class B repeat domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8.1e-06 in 246260 control chromosomes, which does not exceed the estimated maximal expected allele frequency for a pathogenic LDLR variant of (0.0013). c.1502C>T has been reported in the literature in individuals affected with Familial Hypercholesterolemia (Damgaard 2005, Brusgaard 2006, Bertolini 2013, Mabuchi 2014), and was also found in a patient with early-onset myocardial infarction (Do 2015). This variant was identified in once in compound heterozygosity with another pathogenic variant in the LDLR gene (c.718G>A, p.Glu240Lys) in an adult male patient tested on the familal hypercholestolemia panel at our laboratory. No other clinically significant sequence variants were identified in the APOB, LDLR and PCSK9 genes, however no additional familial or clinical information was available. These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and two laboratories classified the variant as likely pathogenic, while one as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Laboratory of Molecular Genetics,National Medical Research Center for Therapy and Preventive Medicine RCV000770762 SCV001482453 likely pathogenic Familial hypercholesterolemia criteria provided, single submitter research
Invitae RCV000770762 SCV001574238 likely pathogenic Familial hypercholesterolemia 2020-01-29 criteria provided, single submitter clinical testing This sequence change replaces alanine with valine at codon 501 of the LDLR protein (p.Ala501Val). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and valine. This variant is present in population databases (rs755667663, ExAC 0.002%). This variant has been observed in individual(s) with familial hypercholesterolemia or myocardial infarction (PMID: 25014035, 15823288, 23375686, 28932795, 25487149). This variant is also known as A480V in the literature. ClinVar contains an entry for this variant (Variation ID: 251874). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: Deleterious; PolyPhen-2: Possibly Damaging; Align-GVGD: Class C0). This variant disrupts the p.Ala501 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 23375686, 15256764, 16806138, 16205024). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde,Academisch Medisch Centrum RCV000238372 SCV000606444 pathogenic Familial hypercholesterolemia 1 no assertion criteria provided research

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