U.S. flag

An official website of the United States government

NM_000527.5(LDLR):c.1056C>G (p.Cys352Trp) AND Cardiovascular phenotype

Germline classification:
Pathogenic (1 submission)
Last evaluated:
Sep 23, 2019
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:
RCV002401933.2

Allele description

NM_000527.5(LDLR):c.1056C>G (p.Cys352Trp)

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.1056C>G (p.Cys352Trp)
Other names:
FH Avellino-1
HGVS:
  • NC_000019.10:g.11110767C>G
  • NG_009060.1:g.26387C>G
  • NM_000527.5:c.1056C>GMANE SELECT
  • NM_001195798.2:c.1056C>G
  • NM_001195799.2:c.933C>G
  • NM_001195800.2:c.552C>G
  • NM_001195803.2:c.675C>G
  • NP_000518.1:p.Cys352Trp
  • NP_000518.1:p.Cys352Trp
  • NP_001182727.1:p.Cys352Trp
  • NP_001182728.1:p.Cys311Trp
  • NP_001182729.1:p.Cys184Trp
  • NP_001182732.1:p.Cys225Trp
  • LRG_274t1:c.1056C>G
  • LRG_274:g.26387C>G
  • LRG_274p1:p.Cys352Trp
  • NC_000019.9:g.11221443C>G
  • NM_000527.4:c.1056C>G
  • c.1056C>G
  • p.(Cys352Trp)
Protein change:
C184W
Links:
LDLR-LOVD, British Heart Foundation: LDLR_001341; dbSNP: rs13306515
NCBI 1000 Genomes Browser:
rs13306515
Molecular consequence:
  • NM_000527.5:c.1056C>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195798.2:c.1056C>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195799.2:c.933C>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195800.2:c.552C>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195803.2:c.675C>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Cardiovascular phenotype
Identifiers:
MedGen: CN230736

Recent activity

Clear Turn Off Turn On

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...

Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV002712277Ambry Genetics
criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)		Pathogenic
(Sep 23, 2019) 		germlineclinical testing

PubMed (12)
[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 testing for familial hypercholesterolemia: spectrum of LDL receptor gene mutations in The Netherlands.

Lombardi MP, Redeker EJ, Defesche JC, Kamerling SW, Trip MD, Mannens MM, Havekes LM, Kastelein JJ.

Clin Genet. 2000 Feb;57(2):116-24.

PubMed [citation]
PMID:
10735632

Clinical expression of familial hypercholesterolemia in clusters of mutations of the LDL receptor gene that cause a receptor-defective or receptor-negative phenotype.

Bertolini S, Cantafora A, Averna M, Cortese C, Motti C, Martini S, Pes G, Postiglione A, Stefanutti C, Blotta I, Pisciotta L, Rolleri M, Langheim S, Ghisellini M, Rabbone I, Calandra S.

Arterioscler Thromb Vasc Biol. 2000 Sep;20(9):E41-52.

PubMed [citation]
PMID:
10978268
See all PubMed Citations (12)

Details of each submission

From Ambry Genetics, SCV002712277.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (12)

Description

The p.C352W pathogenic mutation (also known as c.1056C>G), located in coding exon 7 of the LDLR gene, results from a C to G substitution at nucleotide position 1056. The cysteine at codon 352 is replaced by tryptophan, an amino acid with highly dissimilar properties, and is located in an EGF-like domain. 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 alteration (also referred to as C331W and FH Avellino-1) has been reported in the homozygous state in a pediatric patient reported to have a clinical diagnosis of homozygous familial hypercholesterolemia (FH) and significantly reduced LDL-receptor activity; however, experimental data were not shown (Bertolini S et al. Arterioscler. Thromb. Vasc. Biol., 1999;19:408-18). This variant has been detected in additional individuals from FH cohorts (Lombardi MP et al. Clin. Genet., 2000;57:116-24; Van Gaal LF et al. Mol. Cell. Probes, 2001;15:329-36; Bertolini S et al. Atherosclerosis, 2013;227:342-8; Gabová D et al. Physiol Res, 2017;66:75-84). Internal structural analysis indicates this alteration eliminates a disulfide bond critical for the structural integrity of the EGF-like 1 domain (Ambry internal data). In addition, other variants affecting this codon (e.g., p.C352Y and p.C352S) have also been reported in association with FH (Magaña Torres MT et al. J Clin Lipidol. 2014;8:525-7; Medeiros AM et al. Genet. Med. 2016;18:316-24). 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 1, 2024