rs879254803

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM2PM5PP3_StrongPP5_Very_Strong

The NM_000527.5(LDLR):c.1135T>C(p.Cys379Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,182 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 Likely pathogenic (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C379Y) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 31)

Consequence

LDLR
NM_000527.5 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:17

Conservation

PhyloP100: 7.83

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 16 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr19-11111589-G-A is described in Lovd as [Likely_pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.995

PP5

Variant 19-11111588-T-C is Pathogenic according to our data. Variant chr19-11111588-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 251685.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-11111588-T-C is described in Lovd as [Pathogenic]. Variant chr19-11111588-T-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LDLR	NM_000527.5 link	c.1135T>C	p.Cys379Arg	missense_variant	Exon 8 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.1135T>C	p.Cys379Arg	missense_variant	Exon 8 of 18	1	NM_000527.5	ENSP00000454071.1		P01130-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152182

Hom.:

Cov.:

show subpopulations

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:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152182

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74346

show subpopulations

Gnomad4 AFR

AF:

0.00

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:

0.00000756

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:17

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hypercholesterolemia, familial, 1

Pathogenic:10

Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Jan 14, 2020

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 25, 2016

LDLR-LOVD, British Heart Foundation

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: literature only

- -

Mar 01, 2016

Fundacion Hipercolesterolemia Familiar

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Mar 01, 2016

Laboratory of Genetics and Molecular Cardiology, University of São Paulo

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Jun 03, 2021

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 18, 2023

All of Us Research Program, National Institutes of Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant (also known as p.Cys358Arg in the mature protein) replaces cysteine with arginine at codon 379 in the EGF-like repeat B of the LDLR protein. 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). Functional studies using patient-derived fibroblasts have shown that this variant causes a significant reduction in LDLR activity in the homozygous state (PMID: 1301956, 9974426). Another functional study using heterozygous patient-derived lymphocytes has shown that this variant causes a significant reduction in residual LDLR activity compared to wild-type (PMID: 21865347). This variant has been reported in over 10 individuals affected with familial hypercholesterolemia (PMID: 11317362, 15241806, 17196209, 25682026, 26342331, 30710474, 32759540, 33955087, 34037665). This variant has also been observed in compound heterozygous and homozygous state in individuals affected with homozygous familial hypercholesterolemia (PMID: 9974426, 1301956, 9974426, 11317362, 15823276, 23375686, 26723464, 27578108, 32977124), indicating that this variant contributes to disease. This variant has been identified in 1/31396 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. -

May 24, 2021

Laboratory of molecular diagnosis of dyslipidemias, Università egli studi di Napoli Federico II

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Reduced activity, in stimulated T-lymphocytes and EBV-transformed B-lymphocytes. -

Feb 14, 2022

Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PS4, PS3, PM2, PP3 -

Jul 07, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Pathogenic:4

May 09, 2023

Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PS3, PP3, PM5, PS4, PM2_SUP -

Apr 14, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Identified in a patient with early-onset myocardial infarction in published literature (Khera et al., 2019); Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies demonstrate a significant reduction in LDL receptor activity (Hobbs et al., 1992); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as p.(C358R); This variant is associated with the following publications: (PMID: 1301956, 34037665, 32759540, 33955087, 30710474, 34040191, 32220565, 26723464, 35379577, 30586733, 32977124, 23375686, 21865347) -

Jan 04, 2024

Clinical Genetics Laboratory, Skane University Hospital Lund

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 05, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The LDLR c.1135T>C; p.Cys379Arg variant (rs879254803), also known as Cys358Arg in legacy nomenclature, is reported in the literature in the heterozygous, homozygous and compound heterozygous sates in numerous individuals affected with familial hypercholesterolemia (Bertolini 2020, Campagna 2008, Hobbs 1992, Sozen 2005, Wang 2020). Fibroblasts/ lymphocytes isolated from homozygous and heterozygous individuals have significantly reduced LDLR activity (Liguori 2001, Romano 2011). This variant is also reported in ClinVar (Variation ID: 251685) and is only observed on one allele in the Genome Aggregation Database, indicating it is not a common polymorphism. The cysteine at codon 379 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.985). Based on available information, this variant is considered to be pathogenic. References: Bertolini S et al. Homozygous familial hypercholesterolemia in Italy: Clinical and molecular features. Atherosclerosis. 2020 Nov;312:72-78. PMID: 32977124. Campagna F et al. Detection of familial hypercholesterolemia in a cohort of children with hypercholesterolemia: results of a family and DNA-based screening. Atherosclerosis. 2008 Jan;196(1):356-364. PMID: 17196209. Hobbs HH et al. Molecular genetics of the LDL receptor gene in familial hypercholesterolemia. Hum Mutat. 1992;1(6):445-66. PMID: 1301956. Liguori R et al. LDL receptor cDNA sequence analysis in familial hypercholesterolemia patients: 5 novel mutations with high prevalence in families originating from southern Italy. Hum Mutat. 2001 May;17(5):433. PMID: 11317362. Romano M et al. An improved method on stimulated T-lymphocytes to functionally characterize novel and known LDLR mutations. J Lipid Res. 2011 Nov;52(11):2095-100. PMID: 21865347. Sozen MM et al. The molecular basis of familial hypercholesterolaemia in Turkish patients. Atherosclerosis. 2005 May;180(1):63-71. PMID: 15823276. Wang H et al. Targeted Genetic Analysis in a Chinese Cohort of 208 Patients Related to Familial Hypercholesterolemia. J Atheroscler Thromb. 2020 Dec 1;27(12):1288-1298. PMID: 32759540. -

Familial hypercholesterolemia

Pathogenic:2

Apr 27, 2023

Color Diagnostics, LLC DBA Color Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Feb 17, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 379 of the LDLR protein (p.Cys379Arg). This variant is present in population databases (no rsID available, gnomAD 0.007%). This missense change has been observed in individuals with hypercholesterolemia (PMID: 9852677, 11317362, 15241806, 23375686, 25682026). It has also been observed to segregate with disease in related individuals. This variant is also known as FH Naples-1 and C358R. ClinVar contains an entry for this variant (Variation ID: 251685). 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%. Experimental studies have shown that this missense change affects LDLR function (PMID: 1301956, 21865347). For these reasons, this variant has been classified as Pathogenic. -

Cardiovascular phenotype

Pathogenic:1

Nov 22, 2022

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.C379R pathogenic mutation (also known as c.1135T>C), located in coding exon 8 of the LDLR gene, results from a T to C substitution at nucleotide position 1135. The cysteine at codon 379 is replaced by arginine, an amino acid with highly dissimilar properties, and is located in the EGF-like B domain. This alteration (with legacy nomenclature p.C358R and FH Naples-1) has been reported in the heterozygous, compound heterozygous, and homozygous states in multiple unrelated individuals with familial hypercholesterolemia (FH) (e.g., Liguori R et al. Hum. Mutat. 2001;17:433; Sözen MM et al. Atherosclerosis. 2005;180:63-71; Campagna F et al. Atherosclerosis. 2008;196:356-64). Fibroblasts derived from several unrelated patients homozygous for this alteration exhibit 15-30% of normal LDLR activity, and lymphocytes obtained from a heterozygous patient also show reduced LDLR activity (Hobbs HH et al. Hum. Mutat. 1992;1:445-66; Bertolini S et al. Arterioscler. Thromb. Vasc. Biol. 1999;19:408-18; Romano M et al. J. Lipid Res. 2011;52:2095-100). Internal structural analysis indicates that this alteration disrupts a disulfide bond known to be crucial for the structural stability of the region (Ambry internal data). Pathogenic LDLR mutations that result in the substitution or generation of cysteine residues within the cysteine-rich LDLR class A repeats and EGF-like domains are common in familial hypercholesterolemia (FH) (Villéger L. Hum Mutat. 2002;20(2):81-7). In addition, a variant at the same codon, p.C379Y, has also been associated with FH (Hirayama T et al. J. Hum. Genet. 1998;43:250-4). In addition, this alteration is predicted to be deleterious by BayesDel in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.58

BayesDel_noAF

Pathogenic

0.60

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.98

D;.;.;.;.;.

Eigen

Pathogenic

0.98

Eigen_PC

Pathogenic

0.85

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.91

D;D;D;D;D;D

M_CAP

Pathogenic

0.96

MetaRNN

Pathogenic

0.99

D;D;D;D;D;D

MetaSVM

Pathogenic

0.95

MutationAssessor

Pathogenic

4.9

H;.;.;.;.;H

PrimateAI

Uncertain

0.74

PROVEAN

Pathogenic

-11

D;D;D;D;D;D

REVEL

Pathogenic

0.98

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

0.99

MutPred

0.98

Gain of disorder (P = 0.0307);Gain of disorder (P = 0.0307);.;.;.;Gain of disorder (P = 0.0307);

MVP

1.0

MPC

1.1

ClinPred

1.0

GERP RS

5.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

1.0

gMVP

1.0

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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