rs185098634

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1PM2PM5PP3_StrongPP5_Strong

The NM_000527.5(LDLR):c.1720C>T(p.Arg574Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000161 in 1,613,906 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 Uncertain significance (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R574H) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000014 ( 0 hom. )

Consequence

LDLR
NM_000527.5 missense

Scores

Clinical Significance

Uncertain significance reviewed by expert panel P:8U:5O:1

Conservation

PhyloP100: 5.95

Variant links:

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]

LDLR links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PM1

In a hotspot region, there are 12 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 7 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 chr19-11116874-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 251996.Status of the report is reviewed_by_expert_panel, 3 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.971

PP5

Variant 19-11116873-C-T is Pathogenic according to our data. Variant chr19-11116873-C-T is described in ClinVar as [Uncertain_significance]. Clinvar id is 183123.Status of the report is reviewed_by_expert_panel, 3 stars. We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=6, Pathogenic=1, Uncertain_significance=5, not_provided=1}. Variant chr19-11116873-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LDLR	NM_000527.5 linkuse as main transcript	c.1720C>T	p.Arg574Cys	missense_variant	12/18	ENST00000558518.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LDLR	ENST00000558518.6 linkuse as main transcript	c.1720C>T	p.Arg574Cys	missense_variant	12/18	1	NM_000527.5	P3	P01130-1

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

152128

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000656

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000318

AC:

AN:

251482

Hom.:

AF XY:

0.0000221

AC XY:

AN XY:

135916

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.0000615

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000144

AC:

AN:

1461660

Hom.:

Cov.:

AF XY:

0.0000193

AC XY:

AN XY:

727122

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.0000126

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.0000328

AC:

AN:

152246

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74434

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000655

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000823

Hom.:

Bravo

AF:

0.0000151

ExAC

AF:

0.0000247

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:8Uncertain:5Other:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Hypercholesterolemia, familial, 1

Pathogenic:4Uncertain:4

Likely pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Jan 08, 2024	This missense variant replaces arginine with cysteine at codon 574 of the LDLR protein. This variant is also known as p.Arg553Cys in the mature protein. This variant alters a conserved arginine residue in the LDLR type B repeat 5 of the LDLR protein (a.a. 572-615), 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). A high-throughput experimental study has shown that this variant may not disrupt LDLR function (PMID: 25647241). This variant has been reported in over 10 individuals affected with familial hypercholesterolemia (PMID: 11462246, 15823288, 19318025, 19446849, 26892515, 27050191, 30293936, 34297352). This variant has been stated to segregate with disease in a German family, although detailed data from the family study has not been provided (PMID: 11462246). This variant has been identified in 10/282878 chromosomes in the general population by the Genome Aggregation Database (gnomAD). A different variant affecting the same codon, p.Arg574His, is considered to be disease-causing (ClinVar variation ID: 251996), suggesting that arginine at this position is important for LDLR protein function. Based on the available evidence, this variant is classified as Likely Pathogenic. -
Uncertain significance, criteria provided, single submitter	research	Fundacion Hipercolesterolemia Familiar	Mar 01, 2016	- -
Pathogenic, no assertion criteria provided	research	Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	-	- -
Uncertain significance, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Jan 22, 2020	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). -
Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory of molecular diagnosis of dyslipidemias, Università egli studi di Napoli Federico II	May 24, 2021	- -
Likely pathogenic, criteria provided, single submitter	literature only	LDLR-LOVD, British Heart Foundation	Mar 25, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix	Dec 16, 2016	subject mutated among 2600 FH index cases screened = 1, family member=1 /FH-Germany/software prediction damaging -
Uncertain significance, reviewed by expert panel	curation	ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	Mar 07, 2022	NM_000527.5(LDLR):c.1720C>T (p.Arg574Cys) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes (PM2, PP3, PP4, PS4_supporting and BS3_supporting) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows: PM2 - PopMax MAF = 0.0001384 (0.01384%) in Other populations exomes+genomes (gnomAD v2.1.1). PP3 - REVEL = 0.967. PP4 - Variant meets PM2. Variant identified in 5 FH cases (1 case with Simon-Broome possible from Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies (APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière); 1 case with Dutch Lipid Clinic Network score greater than or equal to 6 published in PMID: 11462246; 1 case with Dutch Lipid Clinic Network score greater than or equal to 6 published in PMID: 29290422; 1 case with Dutch Lipid Clinic Network score greater than or equal to 6 from Research Lab of Molecular Genetics of Lipid Metabolism - Prof. M.Arca; 1 case with Simon-Broome register possible/definite published in PMID: 26892515. PS4_supporting - Variant meets PM2. Variant identified in 5 unrelated index cases (1 case with Simon-Broome from Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies (APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière); 1 case with Dutch Lipid Clinic Network score greater than or equal to 6 published in PMID: 11462246; 1 case with Dutch Lipid Clinic Network score greater than or equal to 6 published in PMID: 29290422; 1 case with Dutch Lipid Clinic Network score greater than or equal to 6 from Research Lab of Molecular Genetics of Lipid Metabolism - Prof. M.Arca; 1 case with Simon-Broome register criteria published in PMID: 26892515. BS3_supporting - PMID: 25647241: Level 3 assay - study on HeLa-Kyoto cells, LDLR-GFP construct, WB + CLSM assays, whole cycle is above 100% of wild-type activity. - functional study is consistent with no damaging effect. -

Familial hypercholesterolemia

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 16, 2024	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 574 of the LDLR protein (p.Arg574Cys). This variant is present in population databases (rs185098634, gnomAD 0.005%). This missense change has been observed in individuals with hypercholesterolemia (PMID: 11462246, 19446849, 20145306, 23375686, 25487149, 26892515). ClinVar contains an entry for this variant (Variation ID: 183123). 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.Arg574 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 20018285, 22698793, 28028493). 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, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Oct 05, 2023	This missense variant replaces arginine with cysteine at codon 574 of the LDLR protein. This variant is also known as p.Arg553Cys in the mature protein. This variant alters a conserved arginine residue in the LDLR type B repeat 5 of the LDLR protein (a.a. 572-615), 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). A high-throughput experimental study has shown that this variant may not disrupt LDLR function (PMID: 25647241). This variant has been reported in over 10 individuals affected with familial hypercholesterolemia (PMID: 11462246, 15823288, 19318025, 19446849, 26892515, 27050191, 30293936, 34297352). This variant has been stated to segregate with disease in a German family, although detailed data from the family study has not been provided (PMID: 11462246). This variant has been identified in 10/282878 chromosomes in the general population by the Genome Aggregation Database (gnomAD). A different variant affecting the same codon, p.Arg574His, is considered to be disease-causing (ClinVar variation ID: 251996), suggesting that arginine at this position is important for LDLR protein function. Based on the available evidence, this variant is classified as Likely Pathogenic. -

not provided

Pathogenic:1Other:1

Likely pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2018	- -
not provided, no classification provided	in vitro	Dept. of Genetics and Pharmacogenomics, Merck Research Labs	-	- -

Cardiovascular phenotype

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 26, 2020

The p.R574C variant (also known as c.1720C>T), located in coding exon 12 of the LDLR gene, results from a C to T substitution at nucleotide position 1720. The arginine at codon 574 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration has been detected in at least five individuals meeting clinical criteria for familial hypercholesterolemia (FH) as well as once in a cohort of individuals who experienced a myocardial infarction (MI) event before age 50 (Sharifi M et al. Metab. Clin. Exp., 2016 Mar;65:48-53; Thormaehlen AS et al. PLoS Genet., 2015 Feb;11:e1004855; Do R et al. Nature, 2015 Feb;518:102-6; Bertolini S et al. Atherosclerosis, 2013 Apr;227:342-8; Chmara M et al. J. Appl. Genet., 2010;51:95-106; Guardamagna O et al. J. Pediatr., 2009 Aug;155:199-204.e2; Nauck MS et al. Hum. Mutat., 2001 Aug;18:165-6). In addition, a different alteration located at the same position, p.R574S, has been detected in multiple individuals meeting clinical criteria for familial hypercholesterolemia (FH) (Paththinige CS et al. Lipids Health Dis, 2018 May;17:100; Du R et al. Springerplus, 2016 Dec;5:2095; Xiang R et al. Atherosclerosis, 2017 03;258:84-88); Ma Y et al. J Clin Lipidol Oct;12:230-235.e6). 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. -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Aug 09, 2023

Variant summary: LDLR c.1720C>T (p.Arg574Cys) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.2e-05 in 251482 control chromosomes (gnomAD). c.1720C>T has been reported in the literature in many individuals affected with Hypercholesterolemia, primarily in settings of gene or multigene panel testing in large cohorts of patients and in some cases their relatives, but without strong documented evidence of segregation (e.g. Nauck_2001, Damgaard_2005, Bertolini_2013, Trinder_2020, Leren_2021, Noto_2022). These data suggest the variant may be associated with Familial Hypercholesterolemia but do not allow for unequivocal conclusions about variant significance. At least one publication reports experimental evidence evaluating an impact on protein function in a high-throughput in vitro system and found no damaging effect of this variant (e.g. Thormaehlen_2015). Ten submitters, including the ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel, have cited clinical-significance assessments for this variant to ClinVar after 2014 with conflicting assessments. The variant has been classified as either pathogenic (n=1)/likely pathogenic (n=5) or VUS (n=4, including the ClinGen Expert Panel). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.55

BayesDel_addAF

Pathogenic

0.47

BayesDel_noAF

Pathogenic

0.56

Cadd

Pathogenic

Dann

Pathogenic

1.0

DEOGEN2

Pathogenic

0.97

D;.;.;.;.;.

Eigen

Pathogenic

0.82

Eigen_PC

Pathogenic

0.69

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.96

D;D;D;D;D;D

M_CAP

Pathogenic

0.82

MetaRNN

Pathogenic

0.97

D;D;D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.9

H;.;.;.;.;H

MutationTaster

Benign

1.0

D;D;D;D;D;D;D

PrimateAI

Uncertain

0.58

PROVEAN

Pathogenic

-7.6

D;D;D;D;D;D

Sift

Pathogenic

0.0

D;D;D;D;D;D

Sift4G

Pathogenic

0.0

D;D;D;D;D;D

Polyphen

1.0

D;.;.;.;.;.

Vest4

0.90

MVP

1.0

MPC

0.95

ClinPred

1.0

GERP RS

5.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.92

gMVP

0.99

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over