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NM_000527.5(LDLR):c.2000G>A (p.Cys667Tyr) AND Cardiovascular phenotype

Germline classification:
Pathogenic (1 submission)
Last evaluated:
Jun 24, 2024
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:
RCV002415393.3

Allele description [Variation Report for NM_000527.5(LDLR):c.2000G>A (p.Cys667Tyr)]

NM_000527.5(LDLR):c.2000G>A (p.Cys667Tyr)

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.2000G>A (p.Cys667Tyr)
Other names:
C646Y; FH French Canadian 2; FH French Canadian-2; NP_000518.1:p.C667Y; NM_000527.5(LDLR):c.2000G>A
HGVS:
  • NC_000019.10:g.11120382G>A
  • NG_009060.1:g.36002G>A
  • NM_000527.5:c.2000G>AMANE SELECT
  • NM_001195798.2:c.2000G>A
  • NM_001195799.2:c.1877G>A
  • NM_001195800.2:c.1496G>A
  • NM_001195803.2:c.1606+149G>A
  • NP_000518.1:p.Cys667Tyr
  • NP_000518.1:p.Cys667Tyr
  • NP_001182727.1:p.Cys667Tyr
  • NP_001182728.1:p.Cys626Tyr
  • NP_001182729.1:p.Cys499Tyr
  • LRG_274t1:c.2000G>A
  • LRG_274:g.36002G>A
  • LRG_274p1:p.Cys667Tyr
  • NC_000019.9:g.11231058G>A
  • NM_000527.4:c.2000G>A
  • P01130:p.Cys667Tyr
  • c.2000G>A
Protein change:
C499Y; CYS646TYR
Links:
LDLR-LOVD, British Heart Foundation: LDLR_000274; UniProtKB: P01130#VAR_005407; OMIM: 606945.0015; dbSNP: rs28942083
NCBI 1000 Genomes Browser:
rs28942083
Molecular consequence:
  • NM_001195803.2:c.1606+149G>A - intron variant - [Sequence Ontology: SO:0001627]
  • NM_000527.5:c.2000G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195798.2:c.2000G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195799.2:c.1877G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195800.2:c.1496G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Cardiovascular phenotype
Identifiers:
MedGen: CN230736

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV002721678Ambry Genetics
criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)
Pathogenic
(Jun 24, 2024)
germlineclinical testing

PubMed (8)
[See all records that cite these PMIDs]

Citation Link

Summary from all submissions

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

Citations

PubMed

Identification of recurrent and novel mutations in the LDL receptor gene in Spanish patients with familial hypercholesterolemia. Mutations in brief no. 135. Online.

Cenarro A, Jensen HK, Casao E, Civeira F, González-Bonillo J, Rodríguez-Rey JC, Gregersen N, Pocoví M.

Hum Mutat. 1998;11(5):413.

PubMed [citation]
PMID:
10206683

The molecular basis of familial hypercholesterolemia in The Netherlands.

Fouchier SW, Defesche JC, Umans-Eckenhausen MW, Kastelein JP.

Hum Genet. 2001 Dec;109(6):602-15. Epub 2001 Nov 9.

PubMed [citation]
PMID:
11810272
See all PubMed Citations (8)

Details of each submission

From Ambry Genetics, SCV002721678.3

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

Description

The p.C667Y pathogenic mutation (also known as c.2000G>A), located in coding exon 14 of the LDLR gene, results from a G to A substitution at nucleotide position 2000. The cysteine at codon 667 is replaced by tyrosine, an amino acid with highly dissimilar properties. In the original report, this mutation, also known as p.C646Y, was identified as a Class 2 mutation, and in vitro functional analyses indicated this mutation caused significantly decreased LDL receptor activity suggesting abnormal LDL protein folding and transport (Leitersdorf E et al. J Clin Invest. 1990;85(4):1014-23). This mutation has been reported in several patients with familial hypercholesterolemia (FH) (Leitersdorf E et al. J Clin Invest. 1990;85(4):1014-23; Chmara M et al. J Appl Genet. 2010;51(1):95-106; Bertolini S et al. Atherosclerosis. 2013; 227(2):342-8). In one study, this mutation was described in conjunction with another mutation (p.G592E) in LDLR in a compound heterozygous patient with FH who initially presented with planar xanthomas at 6-12 months of age (Kubalska J et al. J Appl Genet. 2008;49(1):109-13). Furthermore, other alterations affecting the same codon (p.C667F c.2000G>T; p.C667R c.1999T>C; p.C667S c.1999T>A; p.C667W c.2001T>G; p.C667* c.2001T>A) have been described in patients with FH (Heath KE et al. Eu J Hum Genet. 2001;9(4):244-52; Vergopoulos A et al. Eur J Hum Genet. 1997;5(5):315-23; Zakharova FM et al. BMC Med Genet. 2005;6:6; Nissen H et al. Clin Genet. 1998;54(1):79-82; Ekstrom U et al. Hum Genet. 1995;96(2):147-50). 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 variant eliminates a disulfide bond critical for the structural integrity of the EGF-like 3 domain (Ambry internal data). 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 supporting evidence, this variant is interpreted as a disease-causing mutation.

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

Last Updated: Sep 29, 2024