rs777188764

Positions:

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PP1_StrongPM2PP3PP4

This summary comes from the ClinGen Evidence Repository: NM_000527.5(LDLR):c.1721G>A (p.Arg574His) variant is classified as Likely pathogenic for Familial Hypercholesterolemia by applying evidence codes (PP1_strong, PM2, PP3 and PP4) 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:PP1_strong - PMID:20018285 - 6 informative meioses in 1 family.PM2 - PopMax MAF = 0.0001129 (0.01129%) in Latino exomes+genomes (gnomAD v2.1.1).PP3 - REVEL = 0.971.PP4 - Variant meets PM2. PMID:20018285 - 1 case with DLCN > 6. LINK:https://erepo.genome.network/evrepo/ui/classification/CA036197/MONDO:0007750/013

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000010 ( 0 hom. )

Consequence

LDLR
ENST00000558518.6 missense

Scores

Clinical Significance

Likely pathogenic reviewed by expert panel P:17U:2

Conservation

PhyloP100: 8.01

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 Likely_pathogenic. Variant got 8 ACMG points.

PM2

For more information check the summary or visit ClinGen Evidence Repository.

PP1

For more information check the summary or visit ClinGen Evidence Repository.

PP3

For more information check the summary or visit ClinGen Evidence Repository.

PP4

For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LDLR	NM_000527.5 linkuse as main transcript	c.1721G>A	p.Arg574His	missense_variant	12/18	ENST00000558518.6	NP_000518.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LDLR	ENST00000558518.6 linkuse as main transcript	c.1721G>A	p.Arg574His	missense_variant	12/18	1	NM_000527.5	ENSP00000454071	P3	P01130-1

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

152104

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000965

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000318

AC:

AN:

251472

Hom.:

AF XY:

0.0000221

AC XY:

AN XY:

135912

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.000116

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000879

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000103

AC:

AN:

1461670

Hom.:

Cov.:

AF XY:

0.00000963

AC XY:

AN XY:

727120

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

Gnomad4 AMR exome

AF:

0.000112

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000719

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000329

AC:

AN:

152104

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74296

show subpopulations

Gnomad4 AFR

AF:

0.0000965

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000416

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:17Uncertain:2

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Hypercholesterolemia, familial, 1

Pathogenic:9Uncertain:2

Uncertain significance, criteria provided, single submitter	research	Fundacion Hipercolesterolemia Familiar	Mar 01, 2016	- -
Likely pathogenic, criteria provided, single submitter	literature only	LDLR-LOVD, British Heart Foundation	Mar 25, 2016	- -
Uncertain significance, criteria provided, single submitter	research	Laboratory of Genetics and Molecular Cardiology, University of São Paulo	Mar 01, 2016	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, Clinical Exome/Genome Diagnostics Group, University Hospital Bonn	Oct 05, 2023	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Juno Genomics, Hangzhou Juno Genomics, Inc	-	PP1_Strong+PP4+PM2_Supporting+PP3 -
Likely pathogenic, criteria provided, single submitter	clinical testing	New York Genome Center	Feb 11, 2020	The c.1721G>A, p.Arg574His variant in the LDLR gene has been observed in individuals affected with familial hypercholesterolemia [PMID: 20018285; PMID: 25461735; PMID: 23375686]. The variant has 0.0031% allele frequency in the gnomAD database (9 out of 282,858 heterozygous alleles), indicating this is a rare allele. In silico tools predict that this variant is likely to be disruptive[https://useast.ensembl.org/info/docs/tools/vep/index.html]. Variants that disrupt the p.Arg574 amino acid residue in LDLR have been observed in individuals affected with familial hypercholesterolemia [PMID: 20018285; PMID: 25461735; PMCID: PMC4766367; PMID: 19446849; PMID: 11462246]. This suggests that it is a clinically significant residue, and that other variants that disrupt this residue are likely to be causative of disease. Based on the available evidence, the c.1721G>A, p.Arg574His variant in the LDLR gene is classified as likely pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Feb 02, 2023	The LDLR c.1721G>A (p.Arg574His) missense variant results in the substitution of arginine at amino acid position 574 with histidine. This variant has been reported in a heterozygous state in at least six probands with hypercholesterolemia (PMID: 20018285; PMID: 35753512; PMID: 23375686; PMID: 33994402; PMID:33740630; PMID: 35339733; PMID: 34037665). The c.1712G>A was reported in a heterozygous state in a 60-year-old female with angina pectoris and pseudoxanthoma elasticum associated with elevated plasma LDL cholesterol levels, who also carried two ABCC6 variants in a compound heterozygous state. The c.1721G>A variant segregated with elevated LDL cholesterol levels in six additional family members (PMID: 20018285). This variant is reported in the Genome Aggregation Database in four alleles at a frequency of 0.000113 in the Latino/Admixed American population (version 2.1.1). Based on the available evidence, the c.1721G>A (p.Arg574His) variant is classified as likely pathogenic for familial hypercholesterolemia. -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	Sep 04, 2023	- -
Likely pathogenic, reviewed by expert panel	curation	ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	Feb 13, 2022	NM_000527.5(LDLR):c.1721G>A (p.Arg574His) variant is classified as Likely pathogenic for Familial Hypercholesterolemia by applying evidence codes (PP1_strong, PM2, PP3 and PP4) 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: PP1_strong - PMID: 20018285 - 6 informative meioses in 1 family. PM2 - PopMax MAF = 0.0001129 (0.01129%) in Latino exomes+genomes (gnomAD v2.1.1). PP3 - REVEL = 0.971. PP4 - Variant meets PM2. PMID: 20018285 - 1 case with DLCN > 6. -
Likely pathogenic, no assertion criteria provided	research	Medical Laboratory Center, Huzhou Maternal and Child Health Hospital	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Jul 29, 2024	This missense variant replaces arginine with histidine at codon 574 of the LDLR protein. This variant is also known as p.Arg553His in the mature protein. This variant alters a conserved arginine residue in the LDLR type B repeat 5 of the EGF precursor homology domain 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. To our knowledge, functional studies have not been performed for this variant. This variant has been reported in at least eight individuals affected with familial hypercholesterolemia (PMID: 20018285, 23375686, 25064003, 25461735, 33740630, 33994402, 34037665, 34314377, 34573395, 35753512; Color internal data). This variant has been identified in 9/282858 chromosomes in the general population by the Genome Aggregation Database (gnomAD). A different missense variant, p.Arg574Cys, is considered to be disease-causing (ClinVar variation ID: 183123), suggesting that arginine at this codon position is important for LDLR protein function. Based on the available evidence, this variant is classified as Likely Pathogenic. -

Familial hypercholesterolemia

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 01, 2023	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 574 of the LDLR protein (p.Arg574His). This variant is present in population databases (rs777188764, gnomAD 0.01%). This missense change has been observed in individuals with familial hypercholesterolemia (PMID: 20018285, 23375686, 25461735; Invitae). ClinVar contains an entry for this variant (Variation ID: 251996). 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: 11462246, 19446849, 20018285, 25461735, 26892515; Invitae). 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	Nov 10, 2023	This missense variant replaces arginine with histidine at codon 574 of the LDLR protein. This variant is also known as p.Arg553His in the mature protein. This variant alters a conserved arginine residue in the LDLR type B repeat 5 of the EGF precursor homology domain 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. To our knowledge, functional studies have not been performed for this variant. This variant has been reported in at least eight individuals affected with familial hypercholesterolemia (PMID: 20018285, 23375686, 25064003, 25461735, 33740630, 33994402, 34037665, 34314377, 34573395, 35753512; Color internal data). This variant has been identified in 9/282858 chromosomes in the general population by the Genome Aggregation Database (gnomAD). A different missense variant, p.Arg574Cys, is considered to be disease-causing (ClinVar variation ID: 183123), suggesting that arginine at this codon position is important for LDLR protein function. Based on the available evidence, this variant is classified as Likely Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	National Institute of Allergy and Infectious Diseases - Centralized Sequencing Program, National Institutes of Health	Aug 06, 2021	- -

not provided

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 20, 2022	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 R553H; This variant is associated with the following publications: (PMID: 22881376, 25064003, 25461735, 33740630, 23375686, 34037665, 20018285) -
Likely pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	LDLR: PM1, PM2, PS4:Moderate, PP4 -

not specified

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Institute for Medical Genetics and Human Genetics, Charité - Universitätsmedizin Berlin

Sep 27, 2022

- -

LDLR-related disorder

Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 13, 2024

The LDLR c.1721G>A variant is predicted to result in the amino acid substitution p.Arg574His. This variant has been observed in multiple individuals affected with familial hypercholesterolemia and segregated with disease in at least one family (see, for example, Pisciotta et al. 2010. PubMed ID: 20018285, Jannes et al. 2015. PubMed ID: 25461735, Bertolini et al. 2013. PubMed ID: 23375686). This variant is reported in 0.011% of alleles in individuals of Latino descent in gnomAD. This variant has been classified as likely pathogenic by the ClinGen Familial Hypercholesterolemia Expert Panel (Clinvar ID: 251996). We interpret this variant as likely pathogenic. -

Cardiovascular phenotype

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 09, 2024

The c.1721G>A (p.R574H) alteration is located in exon 12 (coding exon 12) of the LDLR gene. This alteration results from a G to A substitution at nucleotide position 1721, causing the arginine (R) at amino acid position 574 to be replaced by a histidine (H). This alteration has been detected in several unrelated probands reported to have familial hypercholesterolemia (FH), and has shown segregation with hypercholesterolemia in at least one family (Pisciotta, 2010; Bertolini, 2013; Jannes, 2015; Huang, 2022; Noto, 2022; external communication; Ambry internal data). This amino acid position is highly conserved in available vertebrate species. This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Pathogenic

0.41

BayesDel_noAF

Pathogenic

0.58

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.91

D;.;.;.;.;.

Eigen

Pathogenic

0.81

Eigen_PC

Pathogenic

0.71

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Pathogenic

0.99

D;D;D;D;D;D

M_CAP

Pathogenic

0.77

MetaRNN

Pathogenic

0.99

D;D;D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.4

M;.;.;.;.;M

MutationTaster

Benign

1.0

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

PrimateAI

Uncertain

0.52

PROVEAN

Pathogenic

-4.8

D;D;D;D;D;D

REVEL

Pathogenic

0.97

Sift

Pathogenic

0.0

D;D;D;D;D;D

Sift4G

Uncertain

0.026

D;D;D;D;D;D

Polyphen

1.0

D;.;.;.;.;.

Vest4

0.84

MutPred

0.93

Gain of sheet (P = 0.0221);Gain of sheet (P = 0.0221);.;.;.;Gain of sheet (P = 0.0221);

MVP

1.0

MPC

0.91

ClinPred

0.97

GERP RS

5.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.80

gMVP

0.98

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