ClinVar Miner

Submissions for variant NM_000527.5(LDLR):c.1784G>A (p.Arg595Gln) (rs201102492)

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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
LDLR-LOVD, British Heart Foundation RCV000211609 SCV000295655 likely pathogenic Familial hypercholesterolemia 1 2016-03-25 criteria provided, single submitter literature only
Robarts Research Institute,Western University RCV000211609 SCV000484704 likely pathogenic Familial hypercholesterolemia 1 criteria provided, single submitter clinical testing
Molecular Genetics Laboratory,Centre for Cardiovascular Surgery and Transplantation RCV000211609 SCV000540838 likely pathogenic Familial hypercholesterolemia 1 2016-11-05 criteria provided, single submitter clinical testing
Iberoamerican FH Network RCV000211609 SCV000748100 uncertain significance Familial hypercholesterolemia 1 2016-03-01 criteria provided, single submitter research
Invitae RCV001034677 SCV000752415 pathogenic Familial hypercholesterolemia 2020-09-17 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 595 of the LDLR protein (p.Arg595Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs201102492, ExAC 0.03%). This variant has been reported in several individuals affected with familial hypercholesterolemia (FH) and myocardial infarction and has been described as a common cause of FH in Finland (PMID: 15359125, 15256764, 16250003, 18718593, 25437892, 25487149, 27497240). This variant is also known as p.Arg574Gln and FH-Pogosta in the literature. ClinVar contains an entry for this variant (Variation ID: 183126). Experimental studies have shown that this missense change does not affect LDL uptake in vitro (PMID: 25647241). A different missense substitution at this codon (p.Arg595Trp) has been determined to be pathogenic (PMID: 11737238, 25461735, 27784735, 16250003, 20538126). This suggests that the arginine residue is critical for LDLR protein function and that other missense substitutions at this position may also be pathogenic. For these reasons, this variant has been classified as Pathogenic.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease,Montreal Heart Institute RCV000162002 SCV000987613 pathogenic not provided criteria provided, single submitter clinical testing
Color Health, Inc RCV001034677 SCV001339365 likely pathogenic Familial hypercholesterolemia 2020-07-13 criteria provided, single submitter clinical testing This missense variant (also known as p.Arg574Gln in the mature protein and as FH-Pogosta) is located in the LDLR type B repeat 5 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. An experimental study has shown that this variant causes significant defect in LDL binding, internalization and degradation in cells from a heterozygous carrier (PMID: 11585102). Another study has shown normal LDL uptake in a high throughput screening assay in vitro (PMID: 25647241). This variant has been identified in over 10 individuals affected with familial hypercholesterolemia and myocardial infarction, and reported to be a prevalent mutation in Finland (PMID: 11585102, 15359125, 15256764, 16250003, 18718593, 25437892, 25487149, 27497240). This variant has been identified in 11/282862 chromosomes in the general population by the Genome Aggregation Database (gnomAD). A different missense variant p.Arg595Trp occurring at the same codon is associated with familial hypercholesterolemia (Clinvar), suggesting that arginine at this codon is important for the protein function. Based on available evidence, this variant is classified as Likely Pathogenic.
Laboratory of Molecular Genetics,National Medical Research Center for Therapy and Preventive Medicine RCV001034677 SCV001482457 uncertain significance Familial hypercholesterolemia criteria provided, single submitter research
Mayo Clinic Laboratories, Mayo Clinic RCV000162002 SCV001715496 likely pathogenic not provided 2019-05-05 criteria provided, single submitter clinical testing PS4_moderate, PM1, PM2, PM3, PP3, PP4
Dept. of Genetics and Pharmacogenomics, Merck Research Labs RCV000162002 SCV000189577 not provided not provided no assertion provided in vitro
Cardiovascular Genetics Laboratory,PathWest Laboratory Medicine WA - Fiona Stanley Hospital RCV000211609 SCV000268639 pathogenic Familial hypercholesterolemia 1 2010-09-24 no assertion criteria provided clinical testing
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde,Academisch Medisch Centrum RCV000211609 SCV000606513 pathogenic Familial hypercholesterolemia 1 no assertion criteria provided research

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