ClinVar Miner

Submissions for variant NM_000527.5(LDLR):c.1898G>A (p.Arg633His) (rs754536745)

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Total submissions: 14
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000211621 SCV000285022 likely pathogenic Familial hypercholesterolemia 1 2016-02-25 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 633 of the LDLR protein (p.Arg633His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs754536745, ExAC 0.01%). This variant has been reported in the literature in three patients affected with hypercholesterolemia (PMID: 16250003, 19843101, 15823288). This variant is also known in the literature as R612H. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). A different missense substitution at this codon (p.Arg633Cys) is reported to be deleterious (PMID: 9259195, 15241806, 23375686). This variant is also known in the literature as R612C. This indicates that the arginine residue is important for LDLR protein function. In summary, this is a rare missense change that has been reported in patients affected with hypercholesterolemia and is located in a residue important for LDLR protein function. For these reasons, it has been classified as Likely Pathogenic.
LDLR-LOVD, British Heart Foundation RCV000211621 SCV000295746 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 RCV000211621 SCV000583907 pathogenic Familial hypercholesterolemia 1 2017-03-30 criteria provided, single submitter clinical testing
Fundacion Hipercolesterolemia Familiar RCV000211621 SCV000607654 uncertain significance Familial hypercholesterolemia 1 2016-03-01 criteria provided, single submitter research
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine RCV000211621 SCV000839996 likely pathogenic Familial hypercholesterolemia 1 2017-11-28 criteria provided, single submitter clinical testing The c.1898G>A (p.Arg633His) variant is extremely rare in general population (3 in 246014 by gnomad) and observed in multiple familial hypercholesterolaemia (FH) patients (PMID: 15823288,16250003,19318025). It is predicted to be deleterious by multiple in silica prediction software. The Arg633 is well conserved during evolution. It has been also observed in other clinical labs and reported as pathogenic. At the same position, Arg633Cys variant was observed in multiple FH patient cohort. Based on the above evidences, we interpret this variant as ikely pathogenic.
Department of Human Genetics,Laborarztpraxis Dres. Walther, Weindel und Kollegen RCV000211621 SCV000987029 pathogenic Familial hypercholesterolemia 1 2018-05-23 criteria provided, single submitter clinical testing The nucleotide substitution c.1898G> A causes an exchange of the amino acid arginine to histidine (p.Arg633His). In addition, the mutation described here has already been described in patients with hypercholesterolemia and is therefore classified as pathogenic. The mutation was observed in a patient with TC up to 270 mg/dl and LDL-C approx 230 mg/dl at the age of 45. PMID: 22390909, 16250003, 16250003
CeGaT Praxis fuer Humangenetik Tuebingen RCV001090454 SCV001246011 likely pathogenic not provided 2019-10-01 criteria provided, single submitter clinical testing
Color Health, Inc RCV001188072 SCV001355021 likely pathogenic Familial hypercholesterolemia 2019-06-06 criteria provided, single submitter clinical testing
Invitae RCV001188072 SCV001575965 likely pathogenic Familial hypercholesterolemia 2019-04-29 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 633 of the LDLR protein (p.Arg633His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs754536745, ExAC 0.01%). This variant has been reported in the literature in individuals affected with hypercholesterolemia (PMID: 16250003, 19843101, 15823288). This variant is also known in the literature as R612H. ClinVar contains an entry for this variant (Variation ID: 226380). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: Deleterious; PolyPhen-2: Probably Damaging; Align-GVGD: Class C0). This variant disrupts the p.Arg633 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9259195, 15241806, 23375686). 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.
Laboratory of molecular diagnosis of dyslipidemias, Università egli studi di Napoli Federico II RCV000211621 SCV001653653 likely pathogenic Familial hypercholesterolemia 1 2021-05-24 criteria provided, single submitter clinical testing
Cardiovascular Genetics Laboratory,PathWest Laboratory Medicine WA - Fiona Stanley Hospital RCV000211621 SCV000268649 pathogenic Familial hypercholesterolemia 1 2013-10-30 no assertion criteria provided clinical testing
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde,Academisch Medisch Centrum RCV000211621 SCV000606553 pathogenic Familial hypercholesterolemia 1 no assertion criteria provided research
Broad Institute Rare Disease Group, Broad Institute RCV000211621 SCV001423088 uncertain significance Familial hypercholesterolemia 1 2020-01-22 no assertion criteria provided curation The p.Arg633His variant in LDLR has been reported in at least 3 individuals with Familial Hypercholesterolemia (PMID: 16250003, 15823288, 23375686), and has been identified in 0.009643% (1/10370) of Ashkenazi Jewish chromosomes, 0.006533% (2/30616) of South Asian chromosomes, and 0.002322% (3/129190) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs754536745). 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 as a VUS, likely pathogenic variant, and pathogenic variant in ClinVar (Variation ID: 226380). 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: PP3, PS4_Supporting (Richards 2015).
Natera, Inc. RCV001188072 SCV001461323 likely pathogenic Familial hypercholesterolemia 2020-09-16 no assertion criteria provided clinical testing

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