NM_000298.6(PKLR):c.1529G>A (p.Arg510Gln) AND none provided

Clinical significance:Pathogenic (Last evaluated: Jul 30, 2020)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
1 submission [Details]
Record status:
current
Accession:
RCV001000208.3

Allele description [Variation Report for NM_000298.6(PKLR):c.1529G>A (p.Arg510Gln)]

NM_000298.6(PKLR):c.1529G>A (p.Arg510Gln)

Gene:
PKLR:pyruvate kinase L/R [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
1q22
Genomic location:
Preferred name:
NM_000298.6(PKLR):c.1529G>A (p.Arg510Gln)
HGVS:
  • NC_000001.11:g.155291845C>T
  • NG_011677.1:g.14590G>A
  • NM_000298.6:c.1529G>AMANE SELECT
  • NM_181871.4:c.1436G>A
  • NP_000289.1:p.Arg510Gln
  • NP_870986.1:p.Arg479Gln
  • LRG_1136t1:c.1529G>A
  • LRG_1136:g.14590G>A
  • LRG_1136p1:p.Arg510Gln
  • NC_000001.10:g.155261636C>T
  • NM_000298.5:c.1529G>A
  • P30613:p.Arg510Gln
Protein change:
R479Q; ARG510GLN
Links:
UniProtKB: P30613#VAR_004071; OMIM: 609712.0007; dbSNP: rs113403872
NCBI 1000 Genomes Browser:
rs113403872
Molecular consequence:
  • NM_000298.6:c.1529G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_181871.4:c.1436G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
none provided
Identifiers:
MedGen: CN235283

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV001156713ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratoriescriteria provided, single submitter
Pathogenic
(Jul 30, 2020)
germlineclinical testing

Citation Link

Summary from all submissions

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

Details of each submission

From ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories, SCV001156713.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided

Description

The PKLR c.1529G>A; p.Arg510Gln variant (rs113403872) is reported in both the homozygous or compound heterozygous state in multiple individuals affected with pyruvate kinase deficiency and is considered to be the most common cause of pyruvate kinase deficiency in European populations (Baronciani 1993, Baronciani 1995, Lenzner 1997, van Solinge 1997, van Wijk 2003). Functional analyses of the variant protein shows decreased thermostability, accelerated intracellular proteolytic degradation, and increased susceptibility to ATP inhibition (Lenzner 1997, Wang 2001). This variant is reported as pathogenic by four laboratories in ClinVar (Variation ID: 1511). This variant is found predominantly in the non-Finnish European population with an overall allele frequency of 0.073% (92/126696 alleles, including no homozygotes) in the Genome Aggregation Database. The arginine at codon 510 is highly conserved and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Based on available information, this variant is considered to be pathogenic. References: Baronciani L and Beutler E. Analysis of pyruvate kinase-deficiency mutations that produce nonspherocytic hemolytic anemia. Proc Natl Acad Sci U S A. 1993 May 1;90(9):4324-7. Baronciani L and Beutler E. Molecular study of pyruvate kinase deficient patients with hereditary nonspherocytic hemolytic anemia. J Clin Invest. 1995 Apr;95(4):1702-9. Lenzner C et al. Molecular analysis of 29 pyruvate kinase-deficient patients from central Europe with hereditary hemolytic anemia. Blood. 1997 Mar 1;89(5):1793-9. van Solinge WW et al. Molecular modelling of human red blood cell pyruvate kinase: structural implications of a novel G1091 to a mutation causing severe nonspherocytic hemolytic anemia. Blood. 1997 Dec 15;90(12):4987-95. van Wijk R et al. Disruption of a novel regulatory element in the erythroid-specific promoter of the human PKLR gene causes severe pyruvate kinase deficiency. Blood. 2003 Feb 15;101(4):1596-602. Wang C et al. Human erythrocyte pyruvate kinase: characterization of the recombinant enzyme and a mutant form (R510Q) causing nonspherocytic hemolytic anemia. Blood. 2001 Nov 15;98(10):3113-20.

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

Last Updated: Nov 27, 2021

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