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NM_000527.5(LDLR):c.827G>A (p.Cys276Tyr) AND Cardiovascular phenotype

Germline classification:
Likely pathogenic (1 submission)
Last evaluated:
Mar 26, 2020
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:
RCV002429172.2

Allele description [Variation Report for NM_000527.5(LDLR):c.827G>A (p.Cys276Tyr)]

NM_000527.5(LDLR):c.827G>A (p.Cys276Tyr)

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.827G>A (p.Cys276Tyr)
HGVS:
  • NC_000019.10:g.11107401G>A
  • NG_009060.1:g.23021G>A
  • NM_000527.5:c.827G>AMANE SELECT
  • NM_001195798.2:c.827G>A
  • NM_001195799.2:c.704G>A
  • NM_001195800.2:c.323G>A
  • NM_001195803.2:c.446G>A
  • NP_000518.1:p.Cys276Tyr
  • NP_001182727.1:p.Cys276Tyr
  • NP_001182728.1:p.Cys235Tyr
  • NP_001182729.1:p.Cys108Tyr
  • NP_001182732.1:p.Cys149Tyr
  • LRG_274t1:c.827G>A
  • LRG_274:g.23021G>A
  • NC_000019.9:g.11218077G>A
  • NM_000527.4:c.827G>A
  • P01130:p.Cys276Tyr
  • c.827G>A
Protein change:
C108Y
Links:
LDLR-LOVD, British Heart Foundation: LDLR_000619; UniProtKB: P01130#VAR_005349; dbSNP: rs730882089
NCBI 1000 Genomes Browser:
rs730882089
Molecular consequence:
  • NM_000527.5:c.827G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195798.2:c.827G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195799.2:c.704G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195800.2:c.323G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195803.2:c.446G>A - 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
SCV002680171Ambry Genetics
criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)		Likely pathogenic
(Mar 26, 2020) 		germlineclinical testing

Citation Link

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Details of each submission

From Ambry Genetics, SCV002680171.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided

Description

The p.C276Y variant (also known as c.827G>A), located in coding exon 6 of the LDLR gene, results from a G to A substitution at nucleotide position 827. The cysteine at codon 276 is replaced by tyrosine, 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). In addition, five different alterations located at the same amino acid position (p.C276F, p.C276S, p.C276R, p.C276G, p.C276W) have been detected in LDLR in families with hypercholesterolemia (Klanar G et al. J. Am. Coll. Cardiol., 2015 Sep;66:1250-1257; Thormaehlen AS et al. PLoS Genet., 2015 Feb;11:e1004855; Do R et al. Nature, 2015 Feb;518:102-6; Mozas P et al. Hum. Mutat., 2004 Aug;24:187; Bertolini S et al. Atherosclerosis, 2013 Apr;227:342-8; Martín-Campos JM et al. J Clin Lipidol 2018 Sep;12:1452-1462; Bertolini S et al. Arterioscler. Thromb. Vasc. Biol., 2000 Sep;20:E41-52; Deiana L et al. Arterioscler. Thromb. Vasc. Biol., 2000 Jan;20:236-43). 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 was reported one time in population-based cohorts in the Genome Aggregation Database (gnomAD). 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 7, 2024