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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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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV002634372Ambry Genetics
criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)		Pathogenic
(Mar 31, 2020) 		germlineclinical testing

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

Citation Link

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical 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

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical 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.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Jun 23, 2024