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NM_000527.5(LDLR):c.1130G>A (p.Cys377Tyr) AND Cardiovascular phenotype

Germline classification:
Pathogenic (1 submission)
Last evaluated:
Jun 9, 2017
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:
RCV002321916.2

Allele description [Variation Report for NM_000527.5(LDLR):c.1130G>A (p.Cys377Tyr)]

NM_000527.5(LDLR):c.1130G>A (p.Cys377Tyr)

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.1130G>A (p.Cys377Tyr)
HGVS:
  • NC_000019.10:g.11111583G>A
  • NG_009060.1:g.27203G>A
  • NM_000527.5:c.1130G>AMANE SELECT
  • NM_001195798.2:c.1130G>A
  • NM_001195799.2:c.1007G>A
  • NM_001195800.2:c.626G>A
  • NM_001195803.2:c.749G>A
  • NP_000518.1:p.Cys377Tyr
  • NP_000518.1:p.Cys377Tyr
  • NP_001182727.1:p.Cys377Tyr
  • NP_001182728.1:p.Cys336Tyr
  • NP_001182729.1:p.Cys209Tyr
  • NP_001182732.1:p.Cys250Tyr
  • LRG_274t1:c.1130G>A
  • LRG_274:g.27203G>A
  • LRG_274p1:p.Cys377Tyr
  • NC_000019.9:g.11222259G>A
  • NM_000527.4:c.1130G>A
  • c.1130G>A
Protein change:
C209Y
Links:
LDLR-LOVD, British Heart Foundation: LDLR_000529; dbSNP: rs879254801
NCBI 1000 Genomes Browser:
rs879254801
Molecular consequence:
  • NM_000527.5:c.1130G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195798.2:c.1130G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195799.2:c.1007G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195800.2:c.626G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195803.2:c.749G>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
SCV002610569Ambry Genetics
criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)		Pathogenic
(Jun 9, 2017) 		germlineclinical testing

PubMed (6)
[See all records that cite these PMIDs]

Citation Link

Help

Summary from all submissions

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

Citations

PubMed

Molecular characterization of familial hypercholesterolemia in Spain: identification of 39 novel and 77 recurrent mutations in LDLR.

Mozas P, Castillo S, Tejedor D, Reyes G, Alonso R, Franco M, Saenz P, Fuentes F, Almagro F, Mata P, Pocoví M.

Hum Mutat. 2004 Aug;24(2):187.

PubMed [citation]
PMID:
15241806

An improved method on stimulated T-lymphocytes to functionally characterize novel and known LDLR mutations.

Romano M, Di Taranto MD, Mirabelli P, D'Agostino MN, Iannuzzi A, Marotta G, Gentile M, Raia M, Di Noto R, Del Vecchio L, Rubba P, Fortunato G.

J Lipid Res. 2011 Nov;52(11):2095-100. doi: 10.1194/jlr.D017772. Epub 2011 Aug 24.

PubMed [citation]
PMID:
21865347
PMCID:
PMC3196240
See all PubMed Citations (6)

Details of each submission

From Ambry Genetics, SCV002610569.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (6)

Description

The p.C377Y pathogenic mutation (also known as c.1130G>A), located in coding exon 8 of the LDLR gene, results from a G to A substitution at nucleotide position 1130. The cysteine at codon 377 is replaced by tyrosine, an amino acid with highly dissimilar properties, and is located in the EGF-like B domain. This alteration, also described as p.C356Y, has been identified in several individuals from familial hypercholesterolemia (FH) cohorts (Ekström U et al. Eur. J. Clin. Invest. 1998;28:740-7, Mozas P et al. Hum. Mutat. 2004;24:187, Vandrovcova J et al. Genet. Med. 2013;15:948-57). In addition, alterations involving the same amino acid position, p.C377S (c.1130G>C), p.C377G (c.1129T>G) and p.C377F (c.1130G>T) have been reported in individuals with FH (Bertolini S et al. Atherosclerosis. 2013;227: 342-8, Wu WF et al. PLoS ONE 2014; 9:e94697, Romano M et al, J. Lipid Res. 2011; 52:2095-100). Pathogenic LDLR alterations 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 (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 EGF-like 2 domain (Ambry internal data). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.

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

Last Updated: Feb 25, 2025