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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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002686406	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Likely pathogenic (Jun 27, 2022)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 12436241, 16250003, 21382890, 33508743 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002686406

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Likely pathogenic
(Jun 27, 2022)

germline

clinical testing

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

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical 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

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical 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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: May 7, 2024

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