ClinVar Miner

Submissions for variant NM_000527.4(LDLR):c.1567G>A (p.Val523Met) (rs28942080)

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Total submissions: 16
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Cardiovascular Genetics Laboratory,PathWest Laboratory Medicine WA - Fiona Stanley Hospital RCV000003884 SCV000268622 pathogenic Familial hypercholesterolemia 2013-01-23 no assertion criteria provided 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 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
Color RCV000587718 SCV000909173 likely pathogenic Familial hypercholesterolemias 2018-09-17 criteria provided, single submitter clinical testing Likely Pathogenic variant based on current evidence: This missense variant (also known as p.Val502Met in the mature protein and as FH Kuwait, FH Bari-2) 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 are inconclusive regarding the impact of this variant on the protein function. Computational splicing tools suggest that this variant may not impact the RNA splicing. Experimental functional assays have suggested that this variant causes LDLR recycling defect (PMID: 2088165) and results in a significantly reduced LDLR activity ( This variant has been reported in over 15 European individuals affected with familial hypercholesterolemia (PMID: 7616128, 9974426, 12436241, 15241806, 20045108, 26892515). This variant is rare in the general population and has been identified in 3/246190 chromosomes by the Genome Aggregation Database (gnomAD). Based on available evidence, this variant is classified as Likely Pathogenic.
Dept. of Genetics and Pharmacogenomics, Merck Research Labs RCV000161992 SCV000189567 not provided not provided no assertion provided in vitro
Fundacion Hipercolesterolemia Familiar RCV000003884 SCV000607607 likely pathogenic Familial hypercholesterolemia 2016-03-01 criteria provided, single submitter research
Iberoamerican FH Network RCV000003884 SCV000748098 likely pathogenic Familial hypercholesterolemia 2016-03-01 criteria provided, single submitter research
Integrated Genetics/Laboratory Corporation of America RCV000587718 SCV000697201 pathogenic Familial hypercholesterolemias 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.
Invitae RCV000587718 SCV000940009 likely pathogenic Familial hypercholesterolemias 2018-12-18 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.
LDLR-LOVD, British Heart Foundation RCV000003884 SCV000295499 likely pathogenic Familial hypercholesterolemia 2016-03-25 criteria provided, single submitter literature only
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde,Academisch Medisch Centrum RCV000003884 SCV000606453 pathogenic Familial hypercholesterolemia no assertion criteria provided research
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000825622 SCV000966974 pathogenic Familial hypercholesterolemia - homozygous 2018-07-18 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 hypercholestero lemia as well as in at least 3 homozygous individuals and 3 compound heterozygou s individuals with homozygous familial hypercholesterolemia (Hobbs 1990, Tichy 2 012, Bertolini 2013, Wang 2016, Sanchez-Hernandez 2016, Pirillo 2017). This vari ant also segregated with homozygous familial hypercholesterolemia in 1 homozygou s relative (Bertolini 2013). In vitro functional studies provide some evidence t hat the heterozygous p.Val523Met variant may impact protein function (Romano 201 1). It has been reported in ClinVar (Variation ID: 3696) and has also been ident ified in 1/30782 South Asian and 2/111654 European chromosomes by the Genome Agg regation Database (gnomAD,; dbSNP rs28942080). In summary, this variant meets criteria to be classified as pathogenic for hyper cholesterolemia in an autosomal dominant manner based upon proband count, absenc e from controls, and functional studies. ACMG/AMP Criteria applied: PS4, PM2, PS 3_Supporting, PM3_Strong.
Laboratory of Genetics and Molecular Cardiology,University of São Paulo RCV000003884 SCV000588586 likely pathogenic Familial hypercholesterolemia 2016-03-01 criteria provided, single submitter research
Molecular Genetics Laboratory,Centre for Cardiovascular Surgery and Transplantation RCV000003884 SCV000540825 likely pathogenic Familial hypercholesterolemia 2016-11-05 criteria provided, single submitter clinical testing
OMIM RCV000003884 SCV000024049 pathogenic Familial hypercholesterolemia 2014-08-27 no assertion criteria provided literature only
Robarts Research Institute,Western University RCV000003884 SCV000484683 likely pathogenic Familial hypercholesterolemia criteria provided, single submitter clinical testing
U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille RCV000003884 SCV000583848 pathogenic Familial hypercholesterolemia 2017-03-30 criteria provided, single submitter clinical testing

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