ClinVar Miner

Submissions for variant NM_000527.5(LDLR):c.1720C>T (p.Arg574Cys) (rs185098634)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
LDLR-LOVD, British Heart Foundation RCV000238063 SCV000295611 likely pathogenic Familial hypercholesterolemia 1 2016-03-25 criteria provided, single submitter literature only
Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies,APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix RCV000238063 SCV000503397 uncertain significance Familial hypercholesterolemia 1 2016-12-16 criteria provided, single submitter clinical testing subject mutated among 2600 FH index cases screened = 1, family member=1 /FH-Germany/software prediction damaging
Fundacion Hipercolesterolemia Familiar RCV000238063 SCV000607630 uncertain significance Familial hypercholesterolemia 1 2016-03-01 criteria provided, single submitter research
Invitae RCV000791378 SCV000752408 pathogenic Familial hypercholesterolemia 2019-09-22 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 574 of the LDLR protein (p.Arg574Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs185098634, ExAC 0.02%). This variant has been reported in several individuals affected with hypercholesterolemia (PMID: 11462246, 19446849, 26892515), probable hypercholesterolemia (PMID: 23375686, 20145306), and myocardial infarction (PMID: 25487149). ClinVar contains an entry for this variant (Variation ID: 183123). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. Different missense substitutions at this codon (p.Arg574His, p.Arg574Ser, p.Arg574Leu) have been reported in several individuals affected with hypercholesterolemia (PMID: 28028493, 20018285, 22698793). This suggests that the arginine residue is critical for LDLR protein function. For these reasons, this variant has been classified as Pathogenic.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000161998 SCV001151665 likely pathogenic not provided 2018-10-01 criteria provided, single submitter clinical testing
Color Health, Inc RCV000791378 SCV001349170 likely pathogenic Familial hypercholesterolemia 2019-01-02 criteria provided, single submitter clinical testing
Dept. of Genetics and Pharmacogenomics, Merck Research Labs RCV000161998 SCV000189573 not provided not provided no assertion provided in vitro
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde,Academisch Medisch Centrum RCV000238063 SCV000606498 pathogenic Familial hypercholesterolemia 1 no assertion criteria provided research
Broad Institute Rare Disease Group, Broad Institute RCV000238063 SCV001423052 uncertain significance Familial hypercholesterolemia 1 2020-01-22 no assertion criteria provided curation The p.Arg574Cys variant in LDLR has been reported in 14 individuals with familial hypercholesterolemia (PMID: 29290422, 25647241, 22698793, 20145306, 25487149, 23375686, 11462246, 26892515, 19446849), and has been identified in 0.006% (8/129194) European non-Finnish chromosomes. 0.004% (1/25116) European Finnish chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs185098634). Please note that for diseases with clinical variability, or reduced penetrance, pathogenic variants may be present at a low frequency in the general population. This variant has also been reported in ClinVar as a VUS, likely pathogenic, and pathogenic(Variation ID#: 183123). 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, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PS4_moderate, PM2_supporting, PP3 (Richards 2015).

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