rs113403872

Positions:

chr1-155291845-C-T

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1PM2PP3PP5_Very_Strong

The NM_000298.6(PKLR):c.1529G>A(p.Arg510Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000768 in 1,614,054 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: 𝑓 0.00051 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00079 ( 0 hom. )

Consequence

PKLR
NM_000298.6 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:16

Conservation

PhyloP100: 7.75

Variant links:

Genes affected

PKLR (HGNC:9020): (pyruvate kinase L/R) The protein encoded by this gene is a pyruvate kinase that catalyzes the transphosphorylation of phohsphoenolpyruvate into pyruvate and ATP, which is the rate-limiting step of glycolysis. Defects in this enzyme, due to gene mutations or genetic variations, are the common cause of chronic hereditary nonspherocytic hemolytic anemia (CNSHA or HNSHA). Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

PKLR links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 13 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 3 uncertain in NM_000298.6

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.798

PP5

Variant 1-155291845-C-T is Pathogenic according to our data. Variant chr1-155291845-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 1511.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-155291845-C-T is described in UniProt as null. Variant chr1-155291845-C-T is described in Lovd as [Pathogenic]. Variant chr1-155291845-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PKLR	NM_000298.6 linkuse as main transcript	c.1529G>A	p.Arg510Gln	missense_variant	10/11	ENST00000342741.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PKLR	ENST00000342741.6 linkuse as main transcript	c.1529G>A	p.Arg510Gln	missense_variant	10/11	1	NM_000298.6	P3	P30613-1
PKLR	ENST00000392414.7 linkuse as main transcript	c.1436G>A	p.Arg479Gln	missense_variant	10/11	1		A1	P30613-2

Frequencies

GnomAD3 genomes

AF:

0.000513

AC:

AN:

152136

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000290

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000956

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000358

AC:

AN:

251478

Hom.:

AF XY:

0.000294

AC XY:

AN XY:

135916

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.000738

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.000795

AC:

1162

AN:

1461800

Hom.:

Cov.:

AF XY:

0.000714

AC XY:

519

AN XY:

727206

show subpopulations

Gnomad4 AFR exome

AF:

0.000179

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.00102

Gnomad4 OTH exome

AF:

0.000381

GnomAD4 genome

AF:

0.000512

AC:

AN:

152254

Hom.:

Cov.:

AF XY:

0.000416

AC XY:

AN XY:

74450

show subpopulations

Gnomad4 AFR

AF:

0.000289

Gnomad4 AMR

AF:

0.0000653

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000956

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000638

Hom.:

Bravo

AF:

0.000484

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000930

AC:

ExAC

AF:

0.000404

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.000654

EpiControl

AF:

0.000652

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:16

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:11

Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jun 23, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	May 06, 2021	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 06, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jun 25, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Jul 31, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 25, 2024	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 510 of the PKLR protein (p.Arg510Gln). This variant is present in population databases (rs113403872, gnomAD 0.07%). This missense change has been observed in individual(s) with pyruvate kinase deficiency (PMID: 8483951, 11698298, 18683378, 29396846). ClinVar contains an entry for this variant (Variation ID: 1511). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt PKLR protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects PKLR function (PMID: 11698298). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 29, 2022	Published functional studies demonstrate the R510Q protein has decreased stability toward heat and is more susceptible to ATP inhibition, leading to enzyme instability and decreased enzyme levels in the cell (Wang et al., 2001); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 29610156, 27432187, 27354418, 34662886, 11698298, 18683378, 8483951, 9057665, 29396846, 28760888, 31980526, 32273473, 33193643, 31589614, 33631127) -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2024	PKLR: PM3:Very Strong, PM1, PM2, PP4, PS3:Supporting -
Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Oct 18, 2022	- -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Pyruvate kinase deficiency of red cells

Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	May 15, 2020	This variant has been previously reported as a compound heterozygous and a homozygous change in patients with (PMID: 8483951, 29396846). Functional studies on blood samples from individuals carrying this variant in the compound heterozygous and homozygous state demonstrate reduced pyruvate kinase activity (PMID: 8483951). In vitro studies of the mutant protein reveal that it is unstable and susceptible to ATP inhibition (PMID: 11698298). It is present in the heterozygous state in the gnomAD population database at a frequency of 0.038% (108/282852) and thus is presumed to be rare. The c.1529G>A (p.Arg510Gln) variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. Based on the available evidence, the c.1529G>A (p.Arg510Gln) variant is classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Mar 26, 2024	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Nov 15, 2001	- -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	The c.1529G>A (p.Arg510Gln) variant has been described as the most common pyruvate kinase (PK) deficiency variant in the European population. Across a selection of the available literature, the p.Arg510Gln variant has been identified in at least 43 patients in a homozygous state, 21 patients in a compound heterozygous state, and one patient in a heterozygous state (Baronciani et al. 1993; Baronciani et al. 1995; Lenzner et al. 1997; van Solinge et al. 1997; van Wijk et al. 2003; Rider et al. 2011). Heterozygous parents of the patients, though not affected, were shown to have decreased levels of pyruvate kinase activity (van Solinge et al. 1997). The p.Arg510Gln variant was absent from 150 controls but is reported at a frequency of 0.00093 in the European American population of the Exome Sequencing Project. Functional studies demonstrated that the variant has decreased thermostability, accelerated intracellular proteolytic degradation, and is more susceptible to ATP inhibition (Lenzner et al 1997; Wang et al. 2001). Based on the collective evidence, the p.Arg510Gln variant is classified as pathogenic for pyruvate kinase deficiency. -

PKLR-related disorder

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 06, 2023

The PKLR c.1529G>A variant is predicted to result in the amino acid substitution p.Arg510Gln. This variant has previously been reported to be causative for pyruvate kinase deficiency (Baronciani and Beutler. 1993. PubMed ID: 8483951; Wang et al. 2001. PubMed ID: 11698298). This variant is reported in 0.075% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.48

BayesDel_addAF

Pathogenic

0.28

BayesDel_noAF

Pathogenic

0.55

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.99

D;.

Eigen

Pathogenic

0.92

Eigen_PC

Pathogenic

0.84

FATHMM_MKL

Pathogenic

0.98

M_CAP

Uncertain

0.18

MetaRNN

Pathogenic

0.80

D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.6

H;.

MutationTaster

Benign

1.0

A;A

PrimateAI

Uncertain

0.61

PROVEAN

Uncertain

-3.7

D;D

REVEL

Pathogenic

0.95

Sift

Uncertain

0.023

D;D

Sift4G

Uncertain

0.027

D;D

Polyphen

1.0

D;.

Vest4

0.92

MVP

1.0

MPC

1.4

ClinPred

0.60

GERP RS

4.8

Varity_R

0.95

gMVP

0.97

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over