NM_000527.5(LDLR):c.888C>G (p.Cys296Trp) AND Cardiovascular phenotype

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Jan 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:: RCV002375991.2

Allele description [Variation Report for NM_000527.5(LDLR):c.888C>G (p.Cys296Trp)]

NM_000527.5(LDLR):c.888C>G (p.Cys296Trp)

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.888C>G (p.Cys296Trp)

HGVS:

NC_000019.10:g.11107462C>G
NG_009060.1:g.23082C>G
NM_000527.5:c.888C>GMANE SELECT
NM_001195798.2:c.888C>G
NM_001195799.2:c.765C>G
NM_001195800.2:c.384C>G
NM_001195803.2:c.507C>G
NP_000518.1:p.Cys296Trp
NP_000518.1:p.Cys296Trp
NP_001182727.1:p.Cys296Trp
NP_001182728.1:p.Cys255Trp
NP_001182729.1:p.Cys128Trp
NP_001182732.1:p.Cys169Trp
LRG_274t1:c.888C>G
LRG_274:g.23082C>G
LRG_274p1:p.Cys296Trp
NC_000019.9:g.11218138C>G
NM_000527.4:c.888C>G

Protein change:

C128W

Molecular consequence:

NM_000527.5:c.888C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001195798.2:c.888C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001195799.2:c.765C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001195800.2:c.384C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001195803.2:c.507C>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
SCV002685333	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Likely pathogenic (Jan 15, 2018)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 20809525, 21722902, 23375686 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002685333

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Likely pathogenic
(Jan 15, 2018)

germline

clinical testing

PubMed (3)
[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

Molecular spectrum of autosomal dominant hypercholesterolemia in France.

Marduel M, Carrié A, Sassolas A, Devillers M, Carreau V, Di Filippo M, Erlich D, Abifadel M, Marques-Pinheiro A, Munnich A, Junien C; French ADH Research Network., Boileau C, Varret M, Rabès JP.

Hum Mutat. 2010 Nov;31(11):E1811-24. doi: 10.1002/humu.21348.

PubMed [citation]

PMID:: 20809525
PMCID:: PMC3152176

Mutational analysis of the LDL receptor and APOB genes in Mexican individuals with autosomal dominant hypercholesterolemia.

Vaca G, Vàzquez A, Magaña MT, Ramìrez ML, Dàvalos IP, Martìnez E, Marìn B, Carrillo G.

Atherosclerosis. 2011 Oct;218(2):391-6. doi: 10.1016/j.atherosclerosis.2011.06.006. Epub 2011 Jun 13.

PubMed [citation]

PMID:: 21722902

See all PubMed Citations (3)

Details of each submission

From Ambry Genetics, SCV002685333.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

The p.C296W variant (also known as c.888C>G), located in coding exon 6 of the LDLR gene, results from a C to G substitution at nucleotide position 888. The cysteine at codon 296 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). In addition, internal structural analysis indicates this alteration eliminates a disulfide bond critical for the structural integrity of LDLR class A repeat 7 (Rudenko G et al. Science. 2002 Dec;298(5602):2353-8). Furthermore, other alterations affecting this amino acid (p.C296Y and p.C296S) have been reported in association with FH (Marduel M et al. Hum. Mutat., 2010 Nov;31:E1811-24; Vaca G et al. Atherosclerosis, 2011 Oct;218:391-6; Bertolini S et al. Atherosclerosis, 2013 Apr;227:342-8). 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: Sep 29, 2024

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