ClinVar Miner

Submissions for variant NM_000527.5(LDLR):c.1567G>A (p.Val523Met)

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Total submissions: 19
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
LDLR-LOVD, British Heart Foundation RCV000003884 SCV000295499 likely pathogenic Familial hypercholesterolemia 1 2016-03-25 criteria provided, single submitter literature only
Robarts Research Institute,Western University RCV000003884 SCV000484683 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 RCV000003884 SCV000503365 likely pathogenic Familial hypercholesterolemia 1 2016-12-16 criteria provided, single submitter clinical testing subjects mutated among 2600 FH index cases screened = 2 , family members = 4 with co-segregation / FH-Koweit-Bari,15 to 30% LDLR Activity/Software predictions: Conflicting
Molecular Genetics Laboratory,Centre for Cardiovascular Surgery and Transplantation RCV000003884 SCV000540825 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 RCV000003884 SCV000583848 pathogenic Familial hypercholesterolemia 1 2017-03-30 criteria provided, single submitter clinical testing
Laboratory of Genetics and Molecular Cardiology, University of São Paulo RCV000003884 SCV000588586 likely pathogenic Familial hypercholesterolemia 1 2016-03-01 criteria provided, single submitter research
Fundacion Hipercolesterolemia Familiar RCV000003884 SCV000607607 likely pathogenic Familial hypercholesterolemia 1 2016-03-01 criteria provided, single submitter research
Integrated Genetics/Laboratory Corporation of America RCV000587718 SCV000697201 pathogenic Familial hypercholesterolemia 2016-08-09 criteria provided, single submitter clinical testing Variant summary: The LDLR c.1567G>A (p.Val523Met) 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 2/120764 control chromosomes at a frequency of 0.0000166, which does not exceed the estimated maximal expected allele frequency of a pathogenic LDLR variant (0.0010005). The variant has been reported in numerous affected individuals in the literature in the homozygous and compound heterozygous state. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Iberoamerican FH Network RCV000003884 SCV000748098 likely pathogenic Familial hypercholesterolemia 1 2016-03-01 criteria provided, single submitter research
Color RCV000587718 SCV000909173 pathogenic Familial hypercholesterolemia 2019-09-30 criteria provided, single submitter clinical testing
Invitae RCV000587718 SCV000940009 likely pathogenic Familial hypercholesterolemia 2019-12-30 criteria provided, single submitter clinical testing This sequence change replaces valine with methionine at codon 523 of the LDLR protein (p.Val523Met). The valine residue is highly conserved and there is a small physicochemical difference between valine and methionine. This variant is present in population databases (rs28942080, ExAC 0.006%). This variant has been observed in several individuals affected with familial hypercholesterolemia (PMID: 2088165, 23375686, 21865347, 22294733, 14974088, 15256764, 21310417, 25463123, 27765764). This variant is also known as V502M in the literature. ClinVar contains an entry for this variant (Variation ID: 3696). This variant has been reported not to substantially affect LDLR protein function (PMID: 25647241). This variant disrupts the p.Val523 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been observed in individuals with LDLR-related conditions (PMID: 20809525), which suggests that this may be a clinically significant amino acid residue. 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.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000825622 SCV000966974 pathogenic Homozygous familial hypercholesterolemia 2019-03-26 criteria provided, single submitter clinical testing The p.Val523Met variant in LDLR (also referred as p.Val502Met, FH Kuwait, and FH Bari-2) has been reported in >100 heterozygous individuals with hypercholesterolemia as well as in at least 3 homozygous individuals and 3 compound heterozygous individuals with homozygous familial hypercholesterolemia (Hobbs 1990, Tichy 2012, Bertolini 2013, Wang 2016, Sánchez-Hernández 2016, Pirillo 2017). This variant also segregated with homozygous familial hypercholesterolemia in 1 homozygous relative (Bertolini 2013). In vitro functional studies provide some evidence that the heterozygous p.Val523Met variant may impact protein function (Romano 2011). It has been reported in ClinVar (Variation ID: 3696) and has also been identified in 1/30782 South Asian and 2/111654 European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs28942080). In summary, this variant meets criteria to be classified as pathogenic for familial hypercholesterolemia in an autosomal dominant manner based upon proband count, absence from controls, and functional studies. The ACMG/AMP Criteria applied: PS4, PM2, PS3_Supporting, PM3_Strong.
Institute of Human Genetics,Klinikum rechts der Isar RCV000003884 SCV001430013 pathogenic Familial hypercholesterolemia 1 2018-03-16 criteria provided, single submitter clinical testing
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease,Montreal Heart Institute RCV000003884 SCV001433508 pathogenic Familial hypercholesterolemia 1 2019-04-29 criteria provided, single submitter clinical testing
OMIM RCV000003884 SCV000024049 pathogenic Familial hypercholesterolemia 1 2014-08-27 no assertion criteria provided literature only
Dept. of Genetics and Pharmacogenomics, Merck Research Labs RCV000161992 SCV000189567 not provided not provided no assertion provided in vitro
Cardiovascular Genetics Laboratory,PathWest Laboratory Medicine WA - Fiona Stanley Hospital RCV000003884 SCV000268622 pathogenic Familial hypercholesterolemia 1 2013-01-23 no assertion criteria provided clinical testing
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde,Academisch Medisch Centrum RCV000003884 SCV000606453 pathogenic Familial hypercholesterolemia 1 no assertion criteria provided research
Broad Institute Rare Disease Group,Broad Institute RCV000587718 SCV001422746 likely pathogenic Familial hypercholesterolemia 2020-01-22 no assertion criteria provided curation The p.Val523Met variant in LDLR has been reported in at least 15 individuals with familial hypercholesterolemia (PMID: 15241806, 25463123, 15199436, 9974426, 7616128, 2088165, 21310417, 26892515, 12436241), and has been identified in 0.003% (1/30616) of South Asian chromosomes and 0.002% (2/113644) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs28942080). This variant has also been reported in ClinVar as pathogenic or likely pathogenic (Variation ID: 3696). In vitro functional studies provide some evidence that the p.Val523Met variant may slightly impact protein function (PMID: 25647241, 21865347). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PS4, PP3, PS3_supporting (Richards 2015).

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