1-155290591-C-T

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 4P and 8B. PM1PM5BP4_StrongBS2

The NM_000298.6(PKLR):c.1706G>A(p.Arg569Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00176 in 1,610,328 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R569W) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.0011 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0018 ( 10 hom. )

Consequence

PKLR
NM_000298.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:7

Conservation

PhyloP100: 4.97

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 Likely_benign. Variant got -4 ACMG points.

PM1

In a strand (size 7) in uniprot entity KPYR_HUMAN there are 7 pathogenic changes around while only 0 benign (100%) in NM_000298.6

PM5

Other missense variant is known to change same aminoacid residue: Variant chr1-155290592-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 2434897.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=1}.

BP4

Computational evidence support a benign effect (MetaRNN=0.0575428).

BS2

High Homozygotes in GnomAdExome4 at 10 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PKLR	NM_000298.6 link	c.1706G>A	p.Arg569Gln	missense_variant	Exon 11 of 11	ENST00000342741.6	NP_000289.1	P30613-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PKLR	ENST00000342741.6 link	c.1706G>A	p.Arg569Gln	missense_variant	Exon 11 of 11	1	NM_000298.6	ENSP00000339933.4		P30613-1
PKLR	ENST00000392414.7 link	c.1613G>A	p.Arg538Gln	missense_variant	Exon 11 of 11	1		ENSP00000376214.3		P30613-2

Frequencies

GnomAD3 genomes

AF:

0.00113

AC:

172

AN:

152060

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000217

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000721

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000188

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00218

Gnomad OTH

AF:

0.000958

GnomAD3 exomes

AF:

0.00106

AC:

265

AN:

250772

Hom.:

AF XY:

0.00106

AC XY:

144

AN XY:

135640

show subpopulations

Gnomad AFR exome

AF:

0.000247

Gnomad AMR exome

AF:

0.000578

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000232

Gnomad NFE exome

AF:

0.00204

Gnomad OTH exome

AF:

0.000816

GnomAD4 exome

AF:

0.00182

AC:

2659

AN:

1458150

Hom.:

Cov.:

AF XY:

0.00171

AC XY:

1243

AN XY:

725706

show subpopulations

Gnomad4 AFR exome

AF:

0.000329

Gnomad4 AMR exome

AF:

0.000537

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000263

Gnomad4 NFE exome

AF:

0.00228

Gnomad4 OTH exome

AF:

0.00129

GnomAD4 genome

AF:

0.00113

AC:

172

AN:

152178

Hom.:

Cov.:

AF XY:

0.000968

AC XY:

AN XY:

74392

show subpopulations

Gnomad4 AFR

AF:

0.000217

Gnomad4 AMR

AF:

0.000720

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000188

Gnomad4 NFE

AF:

0.00218

Gnomad4 OTH

AF:

0.000948

Alfa

AF:

0.00187

Hom.:

Bravo

AF:

0.00110

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.00285

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00163

AC:

ExAC

AF:

0.000997

AC:

121

EpiCase

AF:

0.00164

EpiControl

AF:

0.00190

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:5

Nov 29, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The PKLR c.1706G>A; p.Arg569Gln variant (rs61755431, ClinVar Variation ID: 876509) is reported in the compound heterozygous state in individuals with pyruvate kinase (PK) deficiency (Bianchi 2020, Fermo 2005, Lyon 2011, Milanesio 2021, Rab 2021, Van Dooijeweert 2021, van Wijk 2009). However, phasing of the second variant was not confirmed in every individual. In one individual, a second PKLR variant was not detected (Fermo 2005). This variant is found predominantly in the non-Finnish European population with an allele frequency of 0.2% (266/128,632) alleles, including one homozygote) in the Genome Aggregation Database (v2.1.1). Computational analyses predict that this variant is deleterious (REVEL: 0.786). However, given the lack of functional data, the significance of this variant remains uncertain at this time. References: Bianchi P et al. Genotype-phenotype correlation and molecular heterogeneity in pyruvate kinase deficiency. Am J Hematol. 2020 May. PMID: 32043619. Fermo E et al. Red cell pyruvate kinase deficiency: 17 new mutations of the PK-LR gene. Br J Haematol. 2005 Jun. PMID: 15953013. Lyon GJ et al. Exome sequencing and unrelated findings in the context of complex disease research: ethical and clinical implications. Discov Med. 2011 Jul. PMID: 21794208. Milanesio B et al. Six novel variants in the PKLR gene associated with pyruvate kinase deficiency in Argentinian patients. Clin Biochem. 2021 May. PMID: 33631127. Rab MAE et al. AG-348 (Mitapivat), an allosteric activator of red blood cell pyruvate kinase, increases enzymatic activity, protein stability, and ATP levels over a broad range of PKLR genotypes. Haematologica. 2021 Jan 1. PMID: 31974203. Van Dooijeweert B et al. Untargeted metabolic profiling in dried blood spots identifies disease fingerprint for pyruvate kinase deficiency. Haematologica. 2021 Oct 1. PMID: 33054133. van Wijk R et al. Fifteen novel mutations in PKLR associated with pyruvate kinase (PK) deficiency: structural implications of amino acid substitutions in PK. Hum Mutat. 2009 Mar. PMID: 19085939. -

May 08, 2023

Revvity Omics, Revvity

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Dec 19, 2022

Mayo Clinic Laboratories, Mayo Clinic

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PP3 -

Dec 08, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 569 of the PKLR protein (p.Arg569Gln). This variant is present in population databases (rs61755431, gnomAD 0.2%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with clinical features of pyruvate kinase deficiency (PMID: 15953013, 19085939, 21794208, 31974203, 32043619, 33631127). ClinVar contains an entry for this variant (Variation ID: 876509). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt PKLR protein function with a negative predictive value of 80%. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not specified

Uncertain:1

Jul 14, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: PKLR c.1706G>A (p.Arg569Gln) results in a conservative amino acid change located in the Pyruvate kinase, C-terminal domain (IPR015795) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0011 in 250772 control chromosomes in the gnomAD database, including 1 homozygote. This frequency does not allow any conclusion about variant significance. c.1706G>A has been reported in the literature in the compound heterozygous state in individuals affected with various severities of Pyruvate Kinase Deficiency Of Red Cells (e.g. van Wijk_2009, Lyon_2011, Milanesio_2021). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 15953013, 21794208, 33631127, 31974203, 19085939, 32043619). Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -

Pyruvate kinase deficiency of red cells

Uncertain:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.38

BayesDel_addAF

Benign

0.0037

BayesDel_noAF

Pathogenic

0.23

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.94

D;.

Eigen

Uncertain

0.43

Eigen_PC

Uncertain

0.44

FATHMM_MKL

Uncertain

0.95

M_CAP

Uncertain

0.15

MetaRNN

Benign

0.058

T;T

MetaSVM

Pathogenic

0.90

MutationAssessor

Uncertain

2.1

M;.

PrimateAI

Uncertain

0.57

PROVEAN

Uncertain

-3.4

D;D

REVEL

Pathogenic

0.79

Sift

Benign

0.045

D;D

Sift4G

Uncertain

0.043

D;D

Polyphen

0.98

D;.

Vest4

0.74

MVP

0.97

MPC

0.86

ClinPred

0.076

GERP RS

4.5

Varity_R

0.73

gMVP

0.98

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.080

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