rs774723292

Variant names:

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PM1PP3PP4

This summary comes from the ClinGen Evidence Repository: The NM_000527.5(LDLR):c.343C>T (p.Arg115Cys) variant is classified as Likely pathogenic for Familial Hypercholesterolemia by applying evidence codes (PM1, PM2, PP3 and PP4) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1101/2021.03.17.21252755). The supporting evidence is as follows: PM1 - Missense at codon 115. Variant meets PM2 and is in exon 4.PM2 - FAF = 0.0001446 (0.014%) in Latino/Admixed American exomes (gnomAD v2.1.1). PP3 - REVEL = 0.81. PP4 - Variant meets PM2. Identified in at least 1 FH case with clinical diagnosis of definite heterozygous hypercholesterolemia by DLCN score from PMID 16250003. LINK:https://erepo.genome.network/evrepo/ui/classification/CA043225/MONDO:0007750/013

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

LDLR
NM_000527.5 missense

Scores

Clinical Significance

Likely pathogenic reviewed by expert panel P:13U:4

Conservation

PhyloP100: 1.58

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 6 ACMG points.

PM1

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

PM2

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 rank	MANE	Protein	UniProt
LDLR	NM_000527.5 link	c.343C>T	p.Arg115Cys	missense_variant	Exon 4 of 18	ENST00000558518.6	NP_000518.1	P01130-1A0A024R7D5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LDLR	ENST00000558518.6 link	c.343C>T	p.Arg115Cys	missense_variant	Exon 4 of 18	1	NM_000527.5	ENSP00000454071.1		P01130-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000279

AC:

AN:

250716

Hom.:

AF XY:

0.0000295

AC XY:

AN XY:

135750

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000145

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000545

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000883

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000123

AC:

AN:

1461240

Hom.:

Cov.:

AF XY:

0.0000206

AC XY:

AN XY:

726948

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000134

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000809

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000268

Hom.:

Bravo

AF:

0.0000302

ExAC

AF:

0.0000330

AC:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:13Uncertain:4

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Hypercholesterolemia, familial, 1

Pathogenic:9Uncertain:2

Jan 22, 2020

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: curation

The p.Arg115Cys variant in LDLR has been reported in at least 5 individuals (including 1 Dutch individual) with Familial Hypercholesterolemia, segregated with disease in 5 affected relatives from 2 families (PMID: 16250003; Variation ID: 251162), and has been identified in 0.01446% (5/34586) of Latino chromosomes and 0.005446% (1/18362) of East Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs774723292). Although this variant has been seen in the general population, its frequency is not high enough to rule out a pathogenic role. Please note that for diseases with clinical variability, or reduced penetrance, pathogenic variants may be present at a low frequency in the general population. The number of reported affected individuals with this variant is slightly greater than expected compared to non-affected individuals with this variant. This variant has also been reported as a VUS, likely pathogenic variant, and a pathogenic variant in ClinVar (Variation ID: 251162). 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: PP1_Moderate, PP3, PS4_Supporting (Richards 2015). -

Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Mar 25, 2016

LDLR-LOVD, British Heart Foundation

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: literature only

- -

Oct 25, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 07, 2021

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ACMG classification criteria: PS4, PM2, PP1, PP3 -

Dec 16, 2016

Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 12, 2023

Illumina Laboratory Services, Illumina

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The LDLR c.343C>T (p.Arg115Cys) missense variant has been identified in individuals with familial hypercholesterolemia; however, clinical details are limited (PMID:16250003;33418990). This variant is located in the LDLR class A repeat, a component of the well-established ligand (LDL) binding domain within exon 4. The p.Arg115Cys variant results in a substitution of arginine by cysteine, which may affect disulfide bond formation and protein folding (PMID: 34906454). This variant is not observed at a significant frequency in version 2.1.1 or version 3.1.2 of the Genome Aggregation Database. Multiple lines of computational evidence suggest the variant may impact the gene or gene product. The p.Arg115Cys variant has been classified as likely pathogenic by at least three submitters in ClinVar including the ClinGen familial hypercholesterolemia variant curation expert panel. Based on the available evidence, the c.343C>T (p.Arg115Cys) variant is classified as likely pathogenic for familial hypercholesterolemia. -

Mar 30, 2017

U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 07, 2021

ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel

Significance: Likely pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The NM_000527.5(LDLR):c.343C>T (p.Arg115Cys) variant is classified as Likely pathogenic for Familial Hypercholesterolemia by applying evidence codes (PM1, PM2, PP3 and PP4) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1101/2021.03.17.21252755). The supporting evidence is as follows: PM1 - Missense at codon 115. Variant meets PM2 and is in exon 4. PM2 - FAF = 0.0001446 (0.014%) in Latino/Admixed American exomes (gnomAD v2.1.1). PP3 - REVEL = 0.81. PP4 - Variant meets PM2. Identified in at least 1 FH case with clinical diagnosis of definite heterozygous hypercholesterolemia by DLCN score from PMID 16250003. -

Mar 26, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 18, 2024

All of Us Research Program, National Institutes of Health

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces arginine with cysteine at codon 115 of the LDLR protein. This variant is also known as p.Arg94Cys in the mature protein. This variant alters a conserved arginine residue in the type A repeat 3 ligand binding domain of the LDLR protein (a.a. 107-14), where pathogenic missense variants are found enriched (ClinVar-LDLR). Computational prediction tools indicate that this variant has a deleterious impact on protein structure and function. A functional study using a pig model has shown that this variant disrupts LDLR activity (PMID: 10064736). This variant has been reported in individuals affected with familial hypercholesterolemia (PMID: 16250003, 30270359, 34074024, 33418990) in the literature, including three hypercholesterolemic individuals in one family (PMID: 30270359). This variant has also been reported in affected individuals by external laboratories (ClinVar submission SCV000583664.1, SCV000503143.1, SCV001482448.1). This variant has been identified in 7/250716 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -

Familial hypercholesterolemia

Pathogenic:2Uncertain:1

Feb 12, 2025

Color Diagnostics, LLC DBA Color Health

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces arginine with cysteine at codon 115 of the LDLR protein. This variant is also known as p.Arg94Cys in the mature protein. This variant alters a conserved arginine residue in the type A repeat 3 ligand binding domain of the LDLR protein, 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. A functional study using a pig model has shown that this variant disrupts LDLR activity (PMID: 10064736). This variant has been reported in individuals affected with familial hypercholesterolemia (PMID: 16250003, 30270359, 34074024, 33418990) in the literature, including three hypercholesterolemic individuals in one family (PMID: 30270359). This variant has also been reported in affected individuals by external laboratories (ClinVar submission SCV000583664.1, SCV000503143.1, SCV001482448.1). This variant has been identified in 7/250716 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -

Laboratory of Molecular Genetics, National Medical Research Center for Therapy and Preventive Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Jul 13, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 115 of the LDLR protein (p.Arg115Cys). This variant is present in population databases (rs774723292, gnomAD 0.01%). This missense change has been observed in individual(s) with clinical features of LDLR-related conditions (PMID: 16250003, 33418990). ClinVar contains an entry for this variant (Variation ID: 251162). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not provided

Pathogenic:2

Jun 08, 2023

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Reported as likely pathogenic by the ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel in ClinVar (Accession: SCV001960959.1); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 19544207, 10064736, 30270359, 30583242, 34906454, 33418990, 16250003) -

Feb 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

LDLR: PM1, PM2, PS4:Moderate -

Cardiovascular phenotype

Uncertain:1

Mar 05, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.343C>T (p.R115C) alteration is located in exon 4 (coding exon 4) of the LDLR gene. This alteration results from a C to T substitution at nucleotide position 343, causing the arginine (R) at amino acid position 115 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.41

BayesDel_addAF

Pathogenic

0.27

BayesDel_noAF

Pathogenic

0.41

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.85

D;.;.;.

Eigen

Uncertain

0.57

Eigen_PC

Uncertain

0.49

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.96

D;D;D;D

M_CAP

Pathogenic

0.74

MetaRNN

Pathogenic

0.89

D;D;D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Pathogenic

3.4

M;.;.;M

PrimateAI

Benign

0.29

PROVEAN

Uncertain

-3.8

D;D;D;D

REVEL

Pathogenic

0.81

Sift

Uncertain

0.023

D;D;D;D

Sift4G

Uncertain

0.019

D;D;D;D

Polyphen

1.0

D;.;.;.

Vest4

0.50

MVP

1.0

MPC

0.94

ClinPred

0.88

GERP RS

5.3

RBP_binding_hub_radar

0.97

RBP_regulation_power_radar

2.8

Varity_R

0.58

gMVP

0.96

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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