NM_000527.5(LDLR):c.478T>C (p.Cys160Arg) AND Cardiovascular phenotype

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Mar 31, 2020
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV002327176.2

Allele description [Variation Report for NM_000527.5(LDLR):c.478T>C (p.Cys160Arg)]

NM_000527.5(LDLR):c.478T>C (p.Cys160Arg)

Gene:

LDLR:low density lipoprotein receptor [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

19p13.2

Genomic location:

Preferred name:

NM_000527.5(LDLR):c.478T>C (p.Cys160Arg)

HGVS:

NC_000019.10:g.11105384T>C
NG_009060.1:g.21004T>C
NM_000527.5:c.478T>CMANE SELECT
NM_001195798.2:c.478T>C
NM_001195799.2:c.355T>C
NM_001195800.2:c.314-2008T>C
NM_001195803.2:c.314-1181T>C
NP_000518.1:p.Cys160Arg
NP_000518.1:p.Cys160Arg
NP_001182727.1:p.Cys160Arg
NP_001182728.1:p.Cys119Arg
LRG_274t1:c.478T>C
LRG_274:g.21004T>C
LRG_274p1:p.Cys160Arg
NC_000019.9:g.11216060T>C
NM_000527.4:c.478T>C
c.478T>C

Protein change:

C119R

Links:

LDLR-LOVD, British Heart Foundation: LDLR_000721; dbSNP: rs879254540

NCBI 1000 Genomes Browser:

rs879254540

Molecular consequence:

NM_001195800.2:c.314-2008T>C - intron variant - [Sequence Ontology: SO:0001627]
NM_001195803.2:c.314-1181T>C - intron variant - [Sequence Ontology: SO:0001627]
NM_000527.5:c.478T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001195798.2:c.478T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001195799.2:c.355T>C - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Cardiovascular phenotype
Identifiers:: MedGen: CN230736

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002634372	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Pathogenic (Mar 31, 2020)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 12417285, 12436241, 15256764, 16389549 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002634372

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Pathogenic
(Mar 31, 2020)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Molecular genetic analysis of familial hypercholesterolemia: spectrum and regional difference of LDL receptor gene mutations in Japanese population.

Yu W, Nohara A, Higashikata T, Lu H, Inazu A, Mabuchi H.

Atherosclerosis. 2002 Dec;165(2):335-42. Erratum in: Atherosclerosis. 2004 Jun;174(2):399-400.

PubMed [citation]

PMID:: 12417285

Intronic mutations outside of Alu-repeat-rich domains of the LDL receptor gene are a cause of familial hypercholesterolemia.

Amsellem S, Briffaut D, Carrié A, Rabès JP, Girardet JP, Fredenrich A, Moulin P, Krempf M, Reznik Y, Vialettes B, de Gennes JL, Brukert E, Benlian P.

Hum Genet. 2002 Dec;111(6):501-10. Epub 2002 Sep 13.

PubMed [citation]

PMID:: 12436241

See all PubMed Citations (4)

Details of each submission

From Ambry Genetics, SCV002634372.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

The p.C160R pathogenic mutation (also known as c.478T>C), located in coding exon 4 of the LDLR gene, results from a T to C substitution at nucleotide position 478. The cysteine at codon 160, located in LDLR class A repeat 4, is replaced by arginine, an amino acid with highly dissimilar properties. 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). This particular cysteine change, also referred to as C139R, has been detected in individuals from various FH cohorts (Amsellem S et al. Hum. Genet., 2002 Dec;111:501-10; Yu W et al. Atherosclerosis, 2002 Dec;165:335-42; Humphries SE et al. J. Mol. Med., 2006 Mar;84:203-14). Other variants affecting this codon (p.C160Y, p.C160G, and p.C160F) have also been detected in FH cohorts (Day IN et al. Hum. Mutat., 1997;10:116-27; Chakir Kh et al. Mol. Genet. Metab., 1998 Jan;63:31-4; Bourbon M et al. Atherosclerosis, 2017 07;262:8-13). Internal structural analysis indicates this alteration eliminates a disulfide bond critical for the structural integrity of LDLR class A repeat 4 (Ambry internal data). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Jan 13, 2025

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