1-155290591-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 4P and 4B. PM1 PM5 BP4_Strong

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
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:6
• Conservation: PhyloP100: 4.97

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 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=2}.
• BP4: Computational evidence support a benign effect (MetaRNN=0.0575428).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PKLR	NM_000298.6	c.1706G>A	p.Arg569Gln	missense_variant	11/11	ENST00000342741.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PKLR	ENST00000342741.6	c.1706G>A	p.Arg569Gln	missense_variant	11/11	1	NM_000298.6	P3
PKLR	ENST00000392414.7	c.1613G>A	p.Arg538Gln	missense_variant	11/11	1		A1

Frequencies

GnomAD3 genomes AF: 0.00113 AC: 172 AN: 152060 Hom.: 0 Cov.: 31

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.: 1 AF XY: 0.00106 AC XY: 144 AN XY: 135640

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.: 10 Cov.: 29 AF XY: 0.00171 AC XY: 1243 AN XY: 725706

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.: 0 Cov.: 31 AF XY: 0.000968 AC XY: 72 AN XY: 74392

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.: 1

Bravo AF: 0.00110

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00285 AC: 11

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00163 AC: 14

ExAC AF: 0.000997 AC: 121

EpiCase AF: 0.00164

EpiControl AF: 0.00190

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:4

Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	May 11, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	May 08, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Oct 15, 2023	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). 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 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Dec 19, 2022	PP3 -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Jul 14, 2023

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

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

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	T
BayesDel_noAF	Pathogenic	0.23
Cadd	Pathogenic	28
Dann	Pathogenic	1.0
DEOGEN2	Pathogenic	0.94	D;.
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Uncertain	0.95	D
M_CAP	Uncertain	0.15	D
MetaRNN	Benign	0.058	T;T
MetaSVM	Pathogenic	0.90	D
MutationAssessor	Uncertain	2.1	M;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.57	T
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	T
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

Other links and lift over

dbSNP: rs61755431; hg19: chr1-155260382;