NM_000527.5(LDLR):c.267C>G (p.Cys89Trp) AND Cardiovascular phenotype

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Dec 11, 2017
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:: RCV002429167.2

Allele description [Variation Report for NM_000527.5(LDLR):c.267C>G (p.Cys89Trp)]

NM_000527.5(LDLR):c.267C>G (p.Cys89Trp)

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.267C>G (p.Cys89Trp)

HGVS:

NC_000019.10:g.11102740C>G
NG_009060.1:g.18360C>G
NM_000527.5:c.267C>GMANE SELECT
NM_001195798.2:c.267C>G
NM_001195799.2:c.190+2395C>G
NM_001195800.2:c.267C>G
NM_001195803.2:c.267C>G
NP_000518.1:p.Cys89Trp
NP_000518.1:p.Cys89Trp
NP_001182727.1:p.Cys89Trp
NP_001182729.1:p.Cys89Trp
NP_001182732.1:p.Cys89Trp
LRG_274t1:c.267C>G
LRG_274:g.18360C>G
LRG_274p1:p.Cys89Trp
NC_000019.9:g.11213416C>G
NM_000527.4:c.267C>G
c.267C>G

Protein change:

C89W

Links:

LDLR-LOVD, British Heart Foundation: LDLR_000040; dbSNP: rs777640882

NCBI 1000 Genomes Browser:

rs777640882

Molecular consequence:

NM_001195799.2:c.190+2395C>G - intron variant - [Sequence Ontology: SO:0001627]
NM_000527.5:c.267C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001195798.2:c.267C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001195800.2:c.267C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001195803.2:c.267C>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Cardiovascular phenotype
Identifiers:: MedGen: CN230736

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translation factor GUF1, mitochondrial isoform 1 [Homo sapiens]
translation factor GUF1, mitochondrial isoform 1 [Homo sapiens]
gi|157426893|ref|NP_068746.2|

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002743921	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Pathogenic (Dec 11, 2017)	germline	clinical testing	PubMed (13) [See all records that cite these PMIDs] 10208479, 11237541, 11600564, 11668640, 14508510, 15241806, 16627557, 18279815, 18757057, 20144596, 21868016, 22417841, 23997648 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002743921

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Pathogenic
(Dec 11, 2017)

germline

clinical testing

PubMed (13)
[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

The type of mutation in the low density lipoprotein receptor gene influences the cholesterol-lowering response of the HMG-CoA reductase inhibitor simvastatin in patients with heterozygous familial hypercholesterolaemia.

Heath KE, Gudnason V, Humphries SE, Seed M.

Atherosclerosis. 1999 Mar;143(1):41-54.

PubMed [citation]

PMID:: 10208479

Importance of HDL cholesterol levels and the total/ HDL cholesterol ratio as a risk factor for coronary heart disease in molecularly defined heterozygous familial hypercholesterolaemia.

Real JT, Chaves FJ, Martínez-Usó I, García-García AB, Ascaso JF, Carmena R.

Eur Heart J. 2001 Mar;22(6):465-71.

PubMed [citation]

PMID:: 11237541

See all PubMed Citations (13)

Details of each submission

From Ambry Genetics, SCV002743921.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (13)

Description

The p.C89W pathogenic mutation (also known as c.267C>G), located in coding exon 3 of the LDLR gene, results from a C to G substitution at nucleotide position 267. The cysteine at codon 89 is replaced by tryptophan, an amino acid with highly dissimilar properties. This alteration has been detected in several individuals with familial hypercholesterolemia (FH) and has been shown to segregrate with disease in two families (Heath KE et al. Atherosclerosis. 1999;143:41-54; Chaves FJ et al. J. Clin. Endocrinol. Metab. 2001;86:4926-32; Jelassi A et al. Atherosclerosis. 2009;203:449-53; Garcia-Garcia AB et al. Atherosclerosis. 2011;218:423-30). In addition, functional studies indicated that this variant causes a reduction in LDLR activity (Garcia-Garcia AB et al. Atherosclerosis. 2011;218:423-30). Three other alterations at the same codon (p.C89R, p.C89G, and p.C89Y) have also been associated with FH (Day IN et al. Hum Mutat. 1997;10(2):116-27; Bertolini S et al. Arterioscler Thromb Vasc Biol. 1999;19(2):408-18; Marduel M et al. Hum Mut. 2010;31(11):E1811-24). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.

#	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 1, 2024

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