NM_000527.5(LDLR):c.463T>C (p.Cys155Arg) AND Cardiovascular phenotype

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: May 20, 2024
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:: RCV002338778.3

Allele description [Variation Report for NM_000527.5(LDLR):c.463T>C (p.Cys155Arg)]

NM_000527.5(LDLR):c.463T>C (p.Cys155Arg)

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.463T>C (p.Cys155Arg)

HGVS:

NC_000019.10:g.11105369T>C
NG_009060.1:g.20989T>C
NM_000527.5:c.463T>CMANE SELECT
NM_001195798.2:c.463T>C
NM_001195799.2:c.340T>C
NM_001195800.2:c.314-2023T>C
NM_001195803.2:c.314-1196T>C
NP_000518.1:p.Cys155Arg
NP_000518.1:p.Cys155Arg
NP_001182727.1:p.Cys155Arg
NP_001182728.1:p.Cys114Arg
LRG_274t1:c.463T>C
LRG_274:g.20989T>C
LRG_274p1:p.Cys155Arg
NC_000019.9:g.11216045T>C
NM_000527.4:c.463T>C
c.463T>C

Protein change:

C114R

Links:

LDLR-LOVD, British Heart Foundation: LDLR_000937; dbSNP: rs879254535

NCBI 1000 Genomes Browser:

rs879254535

Molecular consequence:

NM_001195800.2:c.314-2023T>C - intron variant - [Sequence Ontology: SO:0001627]
NM_001195803.2:c.314-1196T>C - intron variant - [Sequence Ontology: SO:0001627]
NM_000527.5:c.463T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001195798.2:c.463T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001195799.2:c.340T>C - 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
SCV002635279	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Likely pathogenic (May 20, 2024)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 12417285, 15256764, 31947532 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002635279

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Likely pathogenic
(May 20, 2024)

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 genetic analysis of familial hypercholesterolemia: spectrum and regional difference of LDL receptor gene mutations in Japanese population.

Yu W, Nohara A, Higashikata T, Lu H, Inazu A, Mabuchi H.

Atherosclerosis. 2002 Dec;165(2):335-42. Erratum in: Atherosclerosis. 2004 Jun;174(2):399-400.

PubMed [citation]

PMID:: 12417285

Mutations in Japanese subjects with primary hyperlipidemia--results from the Research Committee of the Ministry of Health and Welfare of Japan since 1996--.

Maruyama T, Yamashita S, Matsuzawa Y, Bujo H, Takahashi K, Saito Y, Ishibashi S, Ohashi K, Shionoiri F, Gotoda T, Yamada N, Kita T; Research Committee on Primary Hyperlipidemia of the Ministry of Health and Welfare of Japan..

J Atheroscler Thromb. 2004;11(3):131-45.

PubMed [citation]

PMID:: 15256764

See all PubMed Citations (3)

Details of each submission

From Ambry Genetics, SCV002635279.3

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

Description

The p.C155R variant (also known as c.463T>C), located in coding exon 4 of the LDLR gene, results from a T to C substitution at nucleotide position 463. The cysteine at codon 155, located at LDLR class A repeat 4, is replaced by arginine, 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 was reported in individuals with concerns for FH (Yu W et al. Atherosclerosis, 2002 Dec;165:335-42; Ambry internal data). Internal structural analysis indicates this alteration eliminates a disulfide bond critical for the structural integrity of LDLR class A repeat 4 (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. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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: Aug 11, 2024

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