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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

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV002635322Ambry Genetics
criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)		Likely pathogenic
(Jan 17, 2019) 		germlineclinical testing

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

Citation Link

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical 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

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical 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.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: May 1, 2024