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NM_000527.5(LDLR):c.519C>G (p.Cys173Trp) AND Cardiovascular phenotype

Germline classification:
Pathogenic (1 submission)
Last evaluated:
Feb 8, 2022
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:
RCV002338788.2

Allele description [Variation Report for NM_000527.5(LDLR):c.519C>G (p.Cys173Trp)]

NM_000527.5(LDLR):c.519C>G (p.Cys173Trp)

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.519C>G (p.Cys173Trp)
Other names:
NP_000518.1:p.C173W
HGVS:
  • NC_000019.10:g.11105425C>G
  • NG_009060.1:g.21045C>G
  • NM_000527.5:c.519C>GMANE SELECT
  • NM_001195798.2:c.519C>G
  • NM_001195799.2:c.396C>G
  • NM_001195800.2:c.314-1967C>G
  • NM_001195803.2:c.314-1140C>G
  • NP_000518.1:p.Cys173Trp
  • NP_000518.1:p.Cys173Trp
  • NP_001182727.1:p.Cys173Trp
  • NP_001182728.1:p.Cys132Trp
  • LRG_274t1:c.519C>G
  • LRG_274:g.21045C>G
  • LRG_274p1:p.Cys173Trp
  • NC_000019.9:g.11216101C>G
  • NM_000527.4:c.519C>G
  • P01130:p.Cys173Trp
  • c.519C>G
Protein change:
C132W
Links:
LDLR-LOVD, British Heart Foundation: LDLR_000391; UniProtKB: P01130#VAR_005325; dbSNP: rs769318035
NCBI 1000 Genomes Browser:
rs769318035
Molecular consequence:
  • NM_001195800.2:c.314-1967C>G - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001195803.2:c.314-1140C>G - intron variant - [Sequence Ontology: SO:0001627]
  • NM_000527.5:c.519C>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195798.2:c.519C>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195799.2:c.396C>G - 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
SCV002644198Ambry Genetics
criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)		Pathogenic
(Feb 8, 2022) 		germlineclinical testing

PubMed (8)
[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

Mutation analysis in 46 German families with familial hypercholesterolemia: identification of 8 new mutations. Mutations in brief no. 226. Online.

Ebhardt M, Schmidt H, Doerk T, Tietge U, Haas R, Manns MP, Schmidtke J, Stuhrmann M.

Hum Mutat. 1999;13(3):257.

PubMed [citation]
PMID:
10090484

Identification of recurrent and novel mutations in the LDL receptor gene in German patients with familial hypercholesterolemia.

Nauck MS, Köster W, Dörfer K, Eckes J, Scharnagl H, Gierens H, Nissen H, Nauck MA, Wieland H, März W.

Hum Mutat. 2001 Aug;18(2):165-6.

PubMed [citation]
PMID:
11462246
See all PubMed Citations (8)

Details of each submission

From Ambry Genetics, SCV002644198.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (8)

Description

The p.C173W pathogenic mutation (also known as c.519C>G), located in coding exon 4 of the LDLR gene, results from a C to G substitution at nucleotide position 519. The cysteine at codon 173 is replaced by tryptophan, 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 mutation, which is also known as p.C152W, has been reported in multiple individuals with FH and was observed to segregate with elevated LDL-levels across two generations in one family (Couture P et al. Hum Mutat, 1998;Suppl 1:S226-31; Morash BA et al. Atherosclerosis, 1998 Jan;136:9-16; Ebhardt M et al. Hum Mutat, 1999;13:257; Fouchier SW et al. Hum Genet, 2001 Dec;109:602-15; Nauck MS et al. Hum Mutat, 2001 Aug;18:165-6; Shin DG et al. Atherosclerosis, 2015 Nov;243:53-8; Meshkov A et al. Genes (Basel), 2021 01;12:[ePub ahead of print]; Sturm AC et al. JAMA Cardiol, 2021 08;6:902-909). Internal structural analysis indicates this alteration eliminates a disulfide bond critical for the structural integrity of the LDLR class A repeat 4 (Ambry internal data). 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.

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

Last Updated: Sep 29, 2024