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NM_000527.5(LDLR):c.2042G>A (p.Cys681Tyr) AND Cardiovascular phenotype

Germline classification:
Likely pathogenic (1 submission)
Last evaluated:
Sep 23, 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:
RCV002418065.2

Allele description [Variation Report for NM_000527.5(LDLR):c.2042G>A (p.Cys681Tyr)]

NM_000527.5(LDLR):c.2042G>A (p.Cys681Tyr)

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.2042G>A (p.Cys681Tyr)
HGVS:
  • NC_000019.10:g.11120424G>A
  • NG_009060.1:g.36044G>A
  • NM_000527.5:c.2042G>AMANE SELECT
  • NM_001195798.2:c.2042G>A
  • NM_001195799.2:c.1919G>A
  • NM_001195800.2:c.1538G>A
  • NM_001195803.2:c.1606+191G>A
  • NP_000518.1:p.Cys681Tyr
  • NP_000518.1:p.Cys681Tyr
  • NP_001182727.1:p.Cys681Tyr
  • NP_001182728.1:p.Cys640Tyr
  • NP_001182729.1:p.Cys513Tyr
  • LRG_274t1:c.2042G>A
  • LRG_274:g.36044G>A
  • LRG_274p1:p.Cys681Tyr
  • NC_000019.9:g.11231100G>A
  • NM_000527.4:c.2042G>A
  • c.2042G>A
Protein change:
C513Y
Links:
LDLR-LOVD, British Heart Foundation: LDLR_001591; dbSNP: rs201637900
NCBI 1000 Genomes Browser:
rs201637900
Molecular consequence:
  • NM_001195803.2:c.1606+191G>A - intron variant - [Sequence Ontology: SO:0001627]
  • NM_000527.5:c.2042G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195798.2:c.2042G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195799.2:c.1919G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195800.2:c.1538G>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
SCV002723063Ambry Genetics
criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)		Likely pathogenic
(Sep 23, 2021) 		germlineclinical testing

PubMed (3)
[See all records that cite these PMIDs]

Citation Link

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Summary from all submissions

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

Citations

PubMed

Genetic defects causing familial hypercholesterolaemia: identification of deletions and duplications in the LDL-receptor gene and summary of all mutations found in patients attending the Hammersmith Hospital Lipid Clinic.

Tosi I, Toledo-Leiva P, Neuwirth C, Naoumova RP, Soutar AK.

Atherosclerosis. 2007 Sep;194(1):102-11. Epub 2006 Nov 13.

PubMed [citation]
PMID:
17094996

Genetic causes of familial hypercholesterolaemia in patients in the UK: relation to plasma lipid levels and coronary heart disease risk.

Humphries SE, Whittall RA, Hubbart CS, Maplebeck S, Cooper JA, Soutar AK, Naoumova R, Thompson GR, Seed M, Durrington PN, Miller JP, Betteridge DJ, Neil HA; Simon Broome Familial Hyperlipidaemia Register Group and Scientific Steering Committee..

J Med Genet. 2006 Dec;43(12):943-9. Erratum in: J Med Genet. 2009 Dec;46(12):861. J Med Genet. 2010 Dec;47(12):862.

PubMed [citation]
PMID:
17142622
PMCID:
PMC2563208
See all PubMed Citations (3)

Details of each submission

From Ambry Genetics, SCV002723063.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (3)

Description

The p.C681Y variant (also known as c.2042G>A), located in coding exon 14 of the LDLR gene, results from a G to A substitution at nucleotide position 2042. The cysteine at codon 681, located in the EGF-like 3 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 cysteine alteration (also referred to as p.C660Y) has been detected in individuals from FH cohorts (Schuster H et al. Arterioscler Thromb Vasc Biol, 1995 Dec;15:2176-80; Humphries SE et al. J Med Genet, 2006 Dec;43:943-9; Tosi I et al. Atherosclerosis, 2007 Sep;194:102-11). Internal structural analysis indicates this alteration eliminates a disulfide bond critical for the structural integrity of the EGF-like 3 domain (Ambry internal data). Furthermore, other variants affecting this codon (e.g., p.C681S and p.C681W also referred to as p.C660S and p.C660W, respectively) have also been reported in association with FH (Chiu CY et al. Metabolism. 2005 Aug;54(8):1082-6; Sun XM et al. Atherosclerosis. 1998 Jan;136(1):175-85). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid 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: Sep 29, 2024