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NM_000527.5(LDLR):c.939C>G (p.Cys313Trp) AND Cardiovascular phenotype

Germline classification:
Likely pathogenic (1 submission)
Last evaluated:
Jun 27, 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:
RCV002374402.2

Allele description [Variation Report for NM_000527.5(LDLR):c.939C>G (p.Cys313Trp)]

NM_000527.5(LDLR):c.939C>G (p.Cys313Trp)

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.939C>G (p.Cys313Trp)
HGVS:
  • NC_000019.10:g.11107513C>G
  • NG_009060.1:g.23133C>G
  • NM_000527.5:c.939C>GMANE SELECT
  • NM_001195798.2:c.939C>G
  • NM_001195799.2:c.816C>G
  • NM_001195800.2:c.435C>G
  • NM_001195803.2:c.558C>G
  • NP_000518.1:p.Cys313Trp
  • NP_000518.1:p.Cys313Trp
  • NP_001182727.1:p.Cys313Trp
  • NP_001182728.1:p.Cys272Trp
  • NP_001182729.1:p.Cys145Trp
  • NP_001182732.1:p.Cys186Trp
  • LRG_274t1:c.939C>G
  • LRG_274:g.23133C>G
  • LRG_274p1:p.Cys313Trp
  • NC_000019.9:g.11218189C>G
  • NM_000527.4:c.939C>G
  • c.939C>G
Protein change:
C145W
Links:
LDLR-LOVD, British Heart Foundation: LDLR_001873; dbSNP: rs13306512
NCBI 1000 Genomes Browser:
rs13306512
Molecular consequence:
  • NM_000527.5:c.939C>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195798.2:c.939C>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195799.2:c.816C>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195800.2:c.435C>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195803.2:c.558C>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
SCV002686406Ambry Genetics
criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)		Likely pathogenic
(Jun 27, 2022) 		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

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

Update of the molecular basis of familial hypercholesterolemia in The Netherlands.

Fouchier SW, Kastelein JJ, Defesche JC.

Hum Mutat. 2005 Dec;26(6):550-6.

PubMed [citation]
PMID:
16250003
See all PubMed Citations (4)

Details of each submission

From Ambry Genetics, SCV002686406.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (4)

Description

The p.C313W variant (also known as c.939C>G), located in coding exon 6 of the LDLR gene, results from a C to G substitution at nucleotide position 939. The cysteine at codon 313 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 variant (also referred to as C292W) has been detected in several individuals reported to have FH or from FH cohorts, and has been detected with the LDLR p.K311R variant (Amsellem S et al. Hum Genet, 2002 Dec;111:501-10; Fouchier SW et al. Hum Mutat. 2005 Dec;26(6):550-6; van der Graaf A et al. Circulation, 2011 Mar;123:1167-73; Futema M et al. Atherosclerosis. 2021 02;319:108-117). Another alteration at the same codon, p.C313W (c.938G>A), has been reported in association with FH (Martin R et al. Atherosclerosis. 2016 11;254:8-13). Internal structural analysis indicates this alteration eliminates a disulfide bond critical for the structural integrity of LDLR class A repeat 7 (Ambry internal data). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.

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

Last Updated: Sep 29, 2024