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NM_000527.5(LDLR):c.974G>A (p.Cys325Tyr) AND Cardiovascular phenotype

Germline classification:
Pathogenic (1 submission)
Last evaluated:
Jan 24, 2022
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:
RCV002379058.2

Allele description [Variation Report for NM_000527.5(LDLR):c.974G>A (p.Cys325Tyr)]

NM_000527.5(LDLR):c.974G>A (p.Cys325Tyr)

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.974G>A (p.Cys325Tyr)
Other names:
NM_000527.5(LDLR):c.974G>A; p.Cys325Tyr
HGVS:
  • NC_000019.10:g.11110685G>A
  • NG_009060.1:g.26305G>A
  • NM_000527.5:c.974G>AMANE SELECT
  • NM_001195798.2:c.974G>A
  • NM_001195799.2:c.851G>A
  • NM_001195800.2:c.470G>A
  • NM_001195803.2:c.593G>A
  • NP_000518.1:p.Cys325Tyr
  • NP_000518.1:p.Cys325Tyr
  • NP_001182727.1:p.Cys325Tyr
  • NP_001182728.1:p.Cys284Tyr
  • NP_001182729.1:p.Cys157Tyr
  • NP_001182732.1:p.Cys198Tyr
  • LRG_274t1:c.974G>A
  • LRG_274:g.26305G>A
  • LRG_274p1:p.Cys325Tyr
  • NC_000019.9:g.11221361G>A
  • NM_000527.4:c.974G>A
  • c.974G>A
  • p.(Cys325Tyr)
Protein change:
C157Y
Links:
LDLR-LOVD, British Heart Foundation: LDLR_001893; dbSNP: rs879254746
NCBI 1000 Genomes Browser:
rs879254746
Molecular consequence:
  • NM_000527.5:c.974G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195798.2:c.974G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195799.2:c.851G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195800.2:c.470G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195803.2:c.593G>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
SCV002693914Ambry Genetics
criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)		Pathogenic
(Jan 24, 2022) 		germlineclinical testing

PubMed (10)
[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

Genetic diagnosis of familial hypercholesterolemia using a DNA-array based platform.

Alonso R, Defesche JC, Tejedor D, Castillo S, Stef M, Mata N, Gomez-Enterria P, Martinez-Faedo C, Forga L, Mata P.

Clin Biochem. 2009 Jun;42(9):899-903. doi: 10.1016/j.clinbiochem.2009.01.017. Epub 2009 Feb 6.

PubMed [citation]
PMID:
19318025

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 (10)

Details of each submission

From Ambry Genetics, SCV002693914.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (10)

Description

The p.C325Y pathogenic mutation (also known as c.974G>A), located in coding exon 7 of the LDLR gene, results from a G to A substitution at nucleotide position 974. The cysteine at codon 325, located in the EGF-like 1 domain, 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). This particular alteration has been detected in multiple individuals reported to have familial hypercholesterolemia (FH), and in individuals from FH cohorts (Alonso R et al. Clin Biochem. 2009;42:899-903; Romano M et al. J Lipid Res. 2011;52:2095-100; Hori M et al. Atherosclerosis. 2019 10;289:101-108; Wang H et al. J Atheroscler Thromb. 2020 Dec;27(12):1288-1298; Meshkov A et al. Genes (Basel). 2021 01;12(1); Ambry internal data). Internal structural analysis indicates this alteration eliminates a disulfide bond critical for the structural integrity of the EGF-like 1 domain (Ambry internal data). In a study of patient-derived lymphocytes, this alteration was reported to reduce LDLR activity to approximately 50% of wildtype (Romano M et al. J Lipid Res. 2011;52:2095-100). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition, this alteration is predicted to be deleterious by in silico analysis. 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: Oct 8, 2024