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

gnomAD frequency: 0.00001  dbSNP: rs754536745

Total submissions: 18

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
LDLR-LOVD, British Heart Foundation	RCV000211621	SCV000295746	likely pathogenic	Hypercholesterolemia, familial, 1	2016-03-25	criteria provided, single submitter	literature only
U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille	RCV000211621	SCV000583907	pathogenic	Hypercholesterolemia, familial, 1	2017-03-30	criteria provided, single submitter	clinical testing
Fundacion Hipercolesterolemia Familiar	RCV000211621	SCV000607654	uncertain significance	Hypercholesterolemia, familial, 1	2016-03-01	criteria provided, single submitter	research
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	RCV000211621	SCV000839996	likely pathogenic	Hypercholesterolemia, familial, 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	Hypercholesterolemia, familial, 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 Center for Human Genetics Tuebingen	RCV001090454	SCV001246011	likely pathogenic	not provided	2019-10-01	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001188072	SCV001355021	pathogenic	Familial hypercholesterolemia	2023-09-13	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with histidine at codon 633 of the LDLR protein. This variant is also known as p.Arg612His in the mature protein. This variant alters a conserved arginine residue in the LDLR type B repeat 6 of the EGF precursor homology domain of the LDLR protein (a.a. 616 - 658), where pathogenic missense variants are found enriched (ClinVar-LDLR). Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with familial hypercholesterolemia (PMID: 15823288, 16250003, 20506408, 30270359, 33418990, 34297352, 35928446, 37119068), including in the compound heterozygous state with a second pathogenic LDLR variant in individuals affected with severe homozygous familial hypercholesterolemia (PMID: 26228681, 27784735). This variant has been identified in 6/282886 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Different missense variants affecting the same codon, p.Arg633Cys and p.Arg633Leu, are considered to be disease-causing (ClinVar Variation ID: 226379 and 252107), suggesting that arginine at this position is important for LDLR protein function. Based on the available evidence, this variant is classified as Pathogenic.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000211621	SCV001423088	uncertain significance	Hypercholesterolemia, familial, 1	2020-01-22	criteria provided, single submitter	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).
Labcorp Genetics (formerly Invitae), Labcorp	RCV001188072	SCV001575965	pathogenic	Familial hypercholesterolemia	2024-01-29	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 633 of the LDLR protein (p.Arg633His). This variant is present in population databases (rs754536745, gnomAD 0.01%). This missense change has been observed in individuals with hypercholesterolemia (PMID: 15823288, 16250003, 19843101; Invitae). This variant is also known as R612H. ClinVar contains an entry for this variant (Variation ID: 226380). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt LDLR protein function with a positive predictive value of 95%. 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. For these reasons, this variant has been classified as Pathogenic.
Laboratory of molecular diagnosis of dyslipidemias, Università egli studi di Napoli Federico II	RCV000211621	SCV001653653	likely pathogenic	Hypercholesterolemia, familial, 1	2021-05-24	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002408919	SCV002719220	likely pathogenic	Cardiovascular phenotype	2023-07-19	criteria provided, single submitter	clinical testing	The p.R633H variant (also known as c.1898G>A), located in coding exon 13 of the LDLR gene, results from a G to A substitution at nucleotide position 1898. The arginine at codon 633 is replaced by histidine, an amino acid with highly similar properties. This alteration (also referred to as p.R612H) has been detected in the heterozygous and compound heterozygous states with other LDLR variants in unrelated individuals reported to have heterozygous or homozygous familial hypercholesterolemia (FH), and in FH cohorts with limited detail (Damgaard D et al. Atherosclerosis, 2005 May;180:155-60; Alonso R et al. Clin. Biochem., 2009 Jun;42:899-903; Roeters van Lennep J et al. J Clin Lipidol. 2015 May;9(4):607-17; Sánchez-Hernández RM et al. Circ Cardiovasc Genet, 2016 Dec;9:504-510; Alver M et al. Genet Med. 2019 May;21(5):1173-1180; Meshkov A et al. Genes (Basel). 2021 Jan;12(1); Cuchel M et al. J Am Heart Assoc. 2023 May;12(9):e029175). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Revvity Omics, Revvity	RCV000211621	SCV003830940	likely pathogenic	Hypercholesterolemia, familial, 1	2022-06-13	criteria provided, single submitter	clinical testing
GeneDx	RCV001090454	SCV003918455	likely pathogenic	not provided	2023-04-12	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as p.R612H; This variant is associated with the following publications: (PMID: 22390909, 27578128, 31447099, 16250003, 28235710, 17539906, 9259195, 32719484, 34297352, 33418990, 23375686, 26228681, 20506408, 34037665, 34456049, 19318025, 19843101, 30270359, 15823288, 27784735)
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001090454	SCV004219965	uncertain significance	not provided	2022-11-22	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.000023 (3/129190 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in patients with familial hypercholesterolemia (PMIDs: 15823288 (2005), 16250003 (2005)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV004017507	SCV004847737	likely pathogenic	Homozygous familial hypercholesterolemia	2022-05-12	criteria provided, single submitter	clinical testing	The p.Arg633His variant in LDLR (also described as p.Arg612His in the literature) has been reported in at least 9 individuals with familial hypercholesterolemia (FH), including 2 compound heterozygotes (Fouchier 2005 PMID: 16250003, Damgaard 2005 PMID: 15823288, Huijgen 2012 PMID: 22390909, Alonso 2016 PMID: 27578128, Alver 2019 PMID: 30270359, Meshkov 2020 PMID: 33418990, Sturm 2021 PMID: 34037665). It has also been reported by other clinical laboratories in ClinVar (Variation ID: 226380) and has been identified in 0.007% (2/30616) of South Asian chromosomes by gnomAD (http://gnomad.broadinstitute.org). This frequency is low enough to be consistent with the frequency of FH in the general population. Computational prediction tools and conservation analyses are consistent with pathogenicity. Another variant involving this codon (p.Arg633Cys) has been identified in individuals with FH and is classified as likely pathogenic by this laboratory. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant FH. ACMG/AMP Criteria applied: PM2_Supporting, PM5, PP3, PS4_Moderate.
Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA - Fiona Stanley Hospital	RCV000211621	SCV000268649	pathogenic	Hypercholesterolemia, familial, 1	2013-10-30	no assertion criteria provided	clinical testing
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	RCV000211621	SCV000606553	pathogenic	Hypercholesterolemia, familial, 1		no assertion criteria provided	research
Natera, Inc.	RCV001188072	SCV001461323	likely pathogenic	Familial hypercholesterolemia	2020-09-16	no assertion criteria provided	clinical testing