NM_000527.5(LDLR):c.464G>T (p.Cys155Phe) AND Cardiovascular phenotype

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Jan 17, 2019
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:: RCV002338779.2

Allele description [Variation Report for NM_000527.5(LDLR):c.464G>T (p.Cys155Phe)]

NM_000527.5(LDLR):c.464G>T (p.Cys155Phe)

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.464G>T (p.Cys155Phe)

HGVS:

NC_000019.10:g.11105370G>T
NG_009060.1:g.20990G>T
NM_000527.5:c.464G>TMANE SELECT
NM_001195798.2:c.464G>T
NM_001195799.2:c.341G>T
NM_001195800.2:c.314-2022G>T
NM_001195803.2:c.314-1195G>T
NP_000518.1:p.Cys155Phe
NP_000518.1:p.Cys155Phe
NP_001182727.1:p.Cys155Phe
NP_001182728.1:p.Cys114Phe
LRG_274t1:c.464G>T
LRG_274:g.20990G>T
LRG_274p1:p.Cys155Phe
NC_000019.9:g.11216046G>T
NM_000527.4:c.464G>T
c.464G>T

Protein change:

C114F

Links:

LDLR-LOVD, British Heart Foundation: LDLR_000061; dbSNP: rs879254536

NCBI 1000 Genomes Browser:

rs879254536

Molecular consequence:

NM_001195800.2:c.314-2022G>T - intron variant - [Sequence Ontology: SO:0001627]
NM_001195803.2:c.314-1195G>T - intron variant - [Sequence Ontology: SO:0001627]
NM_000527.5:c.464G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001195798.2:c.464G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001195799.2:c.341G>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Cardiovascular phenotype
Identifiers:: MedGen: CN230736

Recent activity

Clear Turn Off Turn On

Tortricinae 28S ribosomal RNA gene, partial sequence.
Tortricinae 28S ribosomal RNA gene, partial sequence.
PopSet: 375126326

PopSet
twisted [Anopheles coluzzii]
twisted [Anopheles coluzzii]
Gene ID:120949083

Gene
LOC109475325 [Branchiostoma belcheri]
LOC109475325 [Branchiostoma belcheri]
Gene ID:109475325

Gene
Chain Y, Cytochrome c oxidase polypeptide VIIc
Chain Y, Cytochrome c oxidase polypeptide VIIc
gi|149241620|pdb|2EIN|Y

Protein

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

Help

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002635322	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Likely pathogenic (Jan 17, 2019)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002635322

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Likely pathogenic
(Jan 17, 2019)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

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 basis of autosomal dominant hypercholesterolemia: assessment in a large cohort of hypercholesterolemic children.

van der Graaf A, Avis HJ, Kusters DM, Vissers MN, Hutten BA, Defesche JC, Huijgen R, Fouchier SW, Wijburg FA, Kastelein JJ, Wiegman A.

Circulation. 2011 Mar 22;123(11):1167-73. doi: 10.1161/CIRCULATIONAHA.110.979450. Epub 2011 Mar 7.

PubMed [citation]

PMID:: 21382890

Details of each submission

From Ambry Genetics, SCV002635322.2

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

Description

The p.C155F variant (also known as c.464G>T), located in coding exon 4 of the LDLR gene, results from a G to T substitution at nucleotide position 464. The cysteine at codon 155, located at LDLR class A repeat 4, is replaced by phenylalanine, 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 a pediatric FH cohort with limited clinical details provided (van der Graaf A et al. Circulation, 2011 Mar;123:1167-73). Internal structural analysis indicates this alteration eliminates a disulfide bond critical for the structural integrity of LDLR class A repeat 4 (Ambry internal data). Alternate amino acid substitutions at this position, including p.C155G (legacy p.C134G) and p.C155R, have been reported in individuals with FH (Hobbs HH et al. Hum. Mutat., 1992;1:445-66; Lombardi MP et al. Clin. Genet., 2000 Feb;57:116-24; Yu W et al. Atherosclerosis, 2002 Dec;165:335-42). 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 1, 2024

ClinVar

Relating variation to medicine