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NM_000527.5(LDLR):c.590G>A (p.Cys197Tyr) AND Cardiovascular phenotype

Germline classification:
Pathogenic (1 submission)
Last evaluated:
Apr 1, 2021
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:
RCV002354478.2

Allele description [Variation Report for NM_000527.5(LDLR):c.590G>A (p.Cys197Tyr)]

NM_000527.5(LDLR):c.590G>A (p.Cys197Tyr)

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.590G>A (p.Cys197Tyr)
Other names:
FH El Salvador-1; NP_000518.1:p.C197Y
HGVS:
  • NC_000019.10:g.11105496G>A
  • NG_009060.1:g.21116G>A
  • NM_000527.5:c.590G>AMANE SELECT
  • NM_001195798.2:c.590G>A
  • NM_001195799.2:c.467G>A
  • NM_001195800.2:c.314-1896G>A
  • NM_001195803.2:c.314-1069G>A
  • NP_000518.1:p.Cys197Tyr
  • NP_000518.1:p.Cys197Tyr
  • NP_001182727.1:p.Cys197Tyr
  • NP_001182728.1:p.Cys156Tyr
  • LRG_274t1:c.590G>A
  • LRG_274:g.21116G>A
  • LRG_274p1:p.Cys197Tyr
  • NC_000019.9:g.11216172G>A
  • NM_000527.4:c.590G>A
  • NM_000527.5:c.590G>A
  • P01130:p.Cys197Tyr
  • c.590G>A
Protein change:
C156Y
Links:
LDLR-LOVD, British Heart Foundation: LDLR_000081; UniProtKB: P01130#VAR_005329; dbSNP: rs376459828
NCBI 1000 Genomes Browser:
rs376459828
Molecular consequence:
  • NM_001195800.2:c.314-1896G>A - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001195803.2:c.314-1069G>A - intron variant - [Sequence Ontology: SO:0001627]
  • NM_000527.5:c.590G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195798.2:c.590G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195799.2:c.467G>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
SCV002653275Ambry Genetics
criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)		Pathogenic
(Apr 1, 2021) 		germlineclinical testing

PubMed (8)
[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 genetics of the LDL receptor gene in familial hypercholesterolemia.

Hobbs HH, Brown MS, Goldstein JL.

Hum Mutat. 1992;1(6):445-66. Review.

PubMed [citation]
PMID:
1301956

Impact of low-density lipoprotein receptor mutational class on carotid atherosclerosis in patients with familial hypercholesterolemia.

Junyent M, Gilabert R, Jarauta E, Núñez I, Cofán M, Civeira F, Pocoví M, Mallén M, Zambón D, Almagro F, Vega J, Tejedor D, Ros E.

Atherosclerosis. 2010 Feb;208(2):437-41. doi: 10.1016/j.atherosclerosis.2009.07.058. Epub 2009 Aug 8.

PubMed [citation]
PMID:
19717150
See all PubMed Citations (8)

Details of each submission

From Ambry Genetics, SCV002653275.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (8)

Description

The p.C197Y pathogenic mutation (also known as c.590G>A), located in coding exon 4 of the LDLR gene, results from a G to A substitution at nucleotide position 590. The cysteine at codon 197, located in LDLR class A repeat 5, 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, also referred to as FH El Salvador-1 or C176Y, has been reported in individuals with FH and has demonstrated reduced LDLR activity (Hobbs HH et al. Hum. Mutat., 1992;1:445-66; Junyent M et al. Atherosclerosis, 2010 Feb;208:437-41; Chiou KR et al. Am. J. Cardiol., 2010 Jun;105:1752-8; Martinez M et al. Am J Cardiol, 2016 08;118:504-10; Setia N et al. Atherosclerosis, 2016 Dec;255:31-36; Martín-Campos JM et al. J Clin Lipidol 2018 Oct;12:1452-1462). Internal structural analysis indicates this alteration eliminates a disulfide bond critical for the structural integrity of LDLR class A repeat 5. In addition, alterations affecting the same amino acid (C197F, C197W, C197G, C197R) have also been described in FH (Hobbs HH et al. Hum. Mutat., 1992;1:445-66; Chmara M et al. J Appl Genet. 2010;51(1):95-106; Marduel M et al. Hum. Mutat., 2010 Nov;31:E1811-24; Webb JC et al. J. Lipid Res., 1996 Feb;37:368-81). 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 13, 2024