rs754536745

chr19-11120144-G-Achr19-11120144-G-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1 PM2 PM5 PP3_Strong PP5

The NM_000527.5(LDLR):c.1898G>A(p.Arg633His) variant causes a missense change. The variant allele was found at a frequency of 0.0000124 in 1,613,710 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R633C) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: LDLR NM_000527.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:15 U:3
• Conservation: PhyloP100: 4.13

Genes affected

LDLR (HGNC:6547): (low density lipoprotein receptor) The low density lipoprotein receptor (LDLR) gene family consists of cell surface proteins involved in receptor-mediated endocytosis of specific ligands. The encoded protein is normally bound at the cell membrane, where it binds low density lipoprotein/cholesterol and is taken into the cell. Lysosomes release the cholesterol, which is made available for repression of microsomal enzyme 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase, the rate-limiting step in cholesterol synthesis. At the same time, a reciprocal stimulation of cholesterol ester synthesis takes place. Mutations in this gene cause the autosomal dominant disorder, familial hypercholesterolemia. Alternate splicing results in multiple transcript variants.[provided by RefSeq, May 2022]

ACMG classification

Verdict is Pathogenic. Variant got 11 ACMG points.

• PM1: In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 13 uncertain in NM_000527.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr19-11120143-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 226379.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.979
• PP5: Variant 19-11120144-G-A is Pathogenic according to our data. Variant chr19-11120144-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 226380.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=8, Pathogenic=4, Uncertain_significance=3}. Variant chr19-11120144-G-A is described in Lovd as [Pathogenic]. Variant chr19-11120144-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LDLR	NM_000527.5	c.1898G>A	p.Arg633His	missense_variant	13/18	ENST00000558518.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LDLR	ENST00000558518.6	c.1898G>A	p.Arg633His	missense_variant	13/18	1	NM_000527.5	P3

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152102 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000199 AC: 5 AN: 251490 Hom.: 0 AF XY: 0.0000221 AC XY: 3 AN XY: 135918

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000123 AC: 18 AN: 1461608 Hom.: 0 Cov.: 33 AF XY: 0.0000138 AC XY: 10 AN XY: 727128

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000928

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000630

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152102 Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2 AN XY: 74298

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000811 Hom.: 0

Bravo AF: 0.0000113

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:15 Uncertain:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hypercholesterolemia, familial, 1 Pathogenic:8 Uncertain:2

Pathogenic, no assertion criteria provided	research	Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Department of Human Genetics, Laborarztpraxis Dres. Walther, Weindel und Kollegen	May 23, 2018	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 -
Pathogenic, criteria provided, single submitter	clinical testing	U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille	Mar 30, 2017	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory of molecular diagnosis of dyslipidemias, Università egli studi di Napoli Federico II	May 24, 2021	- -
Pathogenic, no assertion criteria provided	clinical testing	Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA - Fiona Stanley Hospital	Oct 30, 2013	- -
Likely pathogenic, criteria provided, single submitter	literature only	LDLR-LOVD, British Heart Foundation	Mar 25, 2016	- -
Uncertain significance, criteria provided, single submitter	research	Fundacion Hipercolesterolemia Familiar	Mar 01, 2016	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jun 13, 2022	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	Nov 28, 2017	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. -
Uncertain significance, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Jan 22, 2020	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). -

Familial hypercholesterolemia Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	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. -
Likely pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Sep 13, 2023	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. -

not provided Pathogenic:2 Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Nov 22, 2022	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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2019	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 12, 2023	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) -

Homozygous familial hypercholesterolemia Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

May 12, 2022

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 phenotype Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 19, 2023

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.51
Cadd	Pathogenic	30
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.91	D;.;.;.;.;.
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D;D;D;D;D
M_CAP	Pathogenic	0.84	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.2	M;.;.;.;.;M
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
PrimateAI	Benign	0.43	T
PROVEAN	Uncertain	-4.4	D;D;D;D;D;D
Sift	Uncertain	0.0010	D;D;D;D;D;D
Sift4G	Uncertain	0.0030	D;D;D;D;D;D
Polyphen		1.0	D;.;.;.;.;.
Vest4		0.63
MutPred		0.91		Loss of methylation at R633 (P = 0.0391);Loss of methylation at R633 (P = 0.0391);.;.;.;Loss of methylation at R633 (P = 0.0391);
MVP		1.0
MPC		0.89
ClinPred		0.92	D
GERP RS		4.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.97
gMVP		0.94

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs754536745; hg19: chr19-11230820; COSMIC: COSV104383862;