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NM_000527.5(LDLR):c.851G>T (p.Cys284Phe) AND Cardiovascular phenotype

Germline classification:
Likely pathogenic (1 submission)
Last evaluated:
Oct 8, 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:
RCV002413905.2

Allele description [Variation Report for NM_000527.5(LDLR):c.851G>T (p.Cys284Phe)]

NM_000527.5(LDLR):c.851G>T (p.Cys284Phe)

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.851G>T (p.Cys284Phe)
HGVS:
  • NC_000019.10:g.11107425G>T
  • NG_009060.1:g.23045G>T
  • NM_000527.5:c.851G>TMANE SELECT
  • NM_001195798.2:c.851G>T
  • NM_001195799.2:c.728G>T
  • NM_001195800.2:c.347G>T
  • NM_001195803.2:c.470G>T
  • NP_000518.1:p.Cys284Phe
  • NP_001182727.1:p.Cys284Phe
  • NP_001182728.1:p.Cys243Phe
  • NP_001182729.1:p.Cys116Phe
  • NP_001182732.1:p.Cys157Phe
  • LRG_274t1:c.851G>T
  • LRG_274:g.23045G>T
  • NC_000019.9:g.11218101G>T
  • NM_000527.4:c.851G>T
Protein change:
C116F
Links:
dbSNP: rs879254694
NCBI 1000 Genomes Browser:
rs879254694
Molecular consequence:
  • NM_000527.5:c.851G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195798.2:c.851G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195799.2:c.728G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195800.2:c.347G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195803.2:c.470G>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
SCV002675456Ambry Genetics
criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)		Likely pathogenic
(Oct 8, 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

Genetic screening of patients with familial hypercholesterolaemia (FH): a New Zealand perspective.

Laurie AD, Scott RS, George PM.

Atheroscler Suppl. 2004 Dec;5(5):13-5.

PubMed [citation]
PMID:
15556094

Details of each submission

From Ambry Genetics, SCV002675456.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)

Description

The p.C284F variant (also known as c.851G>T), located in coding exon 6 of the LDLR gene, results from a G to T substitution at nucleotide position 851. The cysteine at codon 284 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). Internal structural analysis indicates this alteration eliminates a disulfide bond critical for the structural integrity of LDLR class A repeat 7 (Ambry internal data). A different alteration located at the same position, p.C284Y, has been reported in one proband from a Chinese FH cohort (Li JJ et al. Arterioscler. Thromb. Vasc. Biol., 2017 Mar;37:570-579). Additional amino acid substitutions at this codon, p.C284R, p.C284S, and p.C284G, have also been reported in individuals with FH (Wang D et al. J. Hum. Genet., 2001;46:152-4; Leren TP et al. Semin Vasc Med, 2004 Feb;4:75-85; Fouchier SW et al. Hum. Mutat., 2005 Dec;26:550-6). The p.C284F 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