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NM_000527.5(LDLR):c.542C>G (p.Pro181Arg) AND Cardiovascular phenotype

Germline classification:
Uncertain significance (1 submission)
Last evaluated:
Nov 15, 2018
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:
RCV002345556.2

Allele description [Variation Report for NM_000527.5(LDLR):c.542C>G (p.Pro181Arg)]

NM_000527.5(LDLR):c.542C>G (p.Pro181Arg)

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.542C>G (p.Pro181Arg)
Other names:
NM_000527.5(LDLR):c.542C>G
HGVS:
  • NC_000019.10:g.11105448C>G
  • NG_009060.1:g.21068C>G
  • NM_000527.5:c.542C>GMANE SELECT
  • NM_001195798.2:c.542C>G
  • NM_001195799.2:c.419C>G
  • NM_001195800.2:c.314-1944C>G
  • NM_001195803.2:c.314-1117C>G
  • NP_000518.1:p.Pro181Arg
  • NP_000518.1:p.Pro181Arg
  • NP_001182727.1:p.Pro181Arg
  • NP_001182728.1:p.Pro140Arg
  • LRG_274t1:c.542C>G
  • LRG_274:g.21068C>G
  • LRG_274p1:p.Pro181Arg
  • NC_000019.9:g.11216124C>G
  • NM_000527.4:c.542C>G
  • c.542C>G
  • p.(Pro181Arg)
Protein change:
P140R
Links:
LDLR-LOVD, British Heart Foundation: LDLR_000361; dbSNP: rs557344672
NCBI 1000 Genomes Browser:
rs557344672
Molecular consequence:
  • NM_001195800.2:c.314-1944C>G - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001195803.2:c.314-1117C>G - intron variant - [Sequence Ontology: SO:0001627]
  • NM_000527.5:c.542C>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195798.2:c.542C>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195799.2:c.419C>G - missense variant - [Sequence Ontology: SO:0001583]
Functional consequence:
no known functional consequence - Comment(s)

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
SCV002652911Ambry Genetics
criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)		Uncertain significance
(Nov 15, 2018) 		germlineclinical testing

PubMed (5)
[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

Genetic diagnosis of familial hypercholesterolemia in a South European outbreed population: influence of low-density lipoprotein (LDL) receptor gene mutations on treatment response to simvastatin in total, LDL, and high-density lipoprotein cholesterol.

Chaves FJ, Real JT, García-García AB, Civera M, Armengod ME, Ascaso JF, Carmena R.

J Clin Endocrinol Metab. 2001 Oct;86(10):4926-32.

PubMed [citation]
PMID:
11600564

Spectrum of low density lipoprotein receptor mutations in Czech hypercholesterolemic patients.

Kuhrová V, Francová H, Zapletalová P, Freiberger T, Fajkusová L, Hrabincová E, Slováĉková R, Kozák L, Slováková R.

Hum Mutat. 2002 Jan;19(1):80.

PubMed [citation]
PMID:
11754108
See all PubMed Citations (5)

Details of each submission

From Ambry Genetics, SCV002652911.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (5)

Description

The p.P181R variant (also known as c.542C>G), located in coding exon 4 of the LDLR gene, results from a C to G substitution at nucleotide position 542. The proline at codon 181 is replaced by arginine, an amino acid with dissimilar properties. This variant (also described as p.P160R) has been reported in multiple individuals with familial hypercholesterolemia (FH) from a variety of ethnic backgrounds (Chaves FJ et al. J. Clin. Endocrinol. Metab., 2001 Oct;86:4926-32; Kuhrová V et al. Hum. Mutat., 2002 Jan;19:80; Fouchier SW et al. Hum. Mutat., 2005 Dec;26:550-6). In one family with FH, this variant was reported in an asymptomatic proband, as well as in her affected mother and her affected maternal aunt, but was not detected in a second affected maternal aunt (Garcia-Garcia AB et al. Atherosclerosis, 2011 Oct;218:423-30). This variant was also detected in three early onset myocardial infarction (MI) cases and in one non-MI control, but only one of these individuals was reported to have elevated LDL-C levels (Thormaehlen AS et al. PLoS Genet., 2015 Feb;11:e1004855). One functional study suggested this variant affects LDLR processing; however, LDLR activity did not appear to be impacted, and additional in vitro studies showed no significant change in LDL uptake (Garcia-Garcia AB et al. Atherosclerosis, 2011 Oct;218:423-30; Thormaehlen AS et al. PLoS Genet., 2015 Feb;11:e1004855). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is conflicting at this time, the clinical significance of this alteration remains unclear.

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

Last Updated: Oct 13, 2024