rs8177988

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 2P and 8B. PM1BP4_StrongBS2

The NM_000298.6(PKLR):c.1516G>A(p.Val506Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00547 in 1,614,046 control chromosomes in the GnomAD database, including 43 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. V506V) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0041 ( 2 hom., cov: 31)

Exomes 𝑓: 0.0056 ( 41 hom. )

Consequence

PKLR
NM_000298.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7B:4

Conservation

PhyloP100: 3.97

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 -6 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 2 uncertain in NM_000298.6

BP4

Computational evidence support a benign effect (MetaRNN=0.010544926).

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PKLR	NM_000298.6 link	c.1516G>A	p.Val506Ile	missense_variant	Exon 10 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.1516G>A	p.Val506Ile	missense_variant	Exon 10 of 11	1	NM_000298.6	ENSP00000339933.4		P30613-1
PKLR	ENST00000392414.7 link	c.1423G>A	p.Val475Ile	missense_variant	Exon 10 of 11	1		ENSP00000376214.3		P30613-2

Frequencies

GnomAD3 genomes

AF:

0.00413

AC:

629

AN:

152136

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00109

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00537

Gnomad ASJ

AF:

0.00115

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00498

Gnomad FIN

AF:

0.00132

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00653

Gnomad OTH

AF:

0.00765

GnomAD3 exomes

AF:

0.00436

AC:

1096

AN:

251476

Hom.:

AF XY:

0.00493

AC XY:

670

AN XY:

135912

show subpopulations

Gnomad AFR exome

AF:

0.000984

Gnomad AMR exome

AF:

0.00266

Gnomad ASJ exome

AF:

0.00179

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00722

Gnomad FIN exome

AF:

0.00120

Gnomad NFE exome

AF:

0.00606

Gnomad OTH exome

AF:

0.00554

GnomAD4 exome

AF:

0.00561

AC:

8195

AN:

1461792

Hom.:

Cov.:

AF XY:

0.00561

AC XY:

4083

AN XY:

727196

show subpopulations

Gnomad4 AFR exome

AF:

0.000986

Gnomad4 AMR exome

AF:

0.00271

Gnomad4 ASJ exome

AF:

0.00134

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00681

Gnomad4 FIN exome

AF:

0.00140

Gnomad4 NFE exome

AF:

0.00636

Gnomad4 OTH exome

AF:

0.00392

GnomAD4 genome

AF:

0.00413

AC:

629

AN:

152254

Hom.:

Cov.:

AF XY:

0.00394

AC XY:

293

AN XY:

74442

show subpopulations

Gnomad4 AFR

AF:

0.00108

Gnomad4 AMR

AF:

0.00536

Gnomad4 ASJ

AF:

0.00115

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00499

Gnomad4 FIN

AF:

0.00132

Gnomad4 NFE

AF:

0.00653

Gnomad4 OTH

AF:

0.00757

Alfa

AF:

0.00558

Hom.:

Bravo

AF:

0.00434

TwinsUK

AF:

0.00674

AC:

ALSPAC

AF:

0.00519

AC:

ESP6500AA

AF:

0.00159

AC:

ESP6500EA

AF:

0.00512

AC:

ExAC

AF:

0.00419

AC:

509

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00676

EpiControl

AF:

0.00747

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:7Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:5Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jun 12, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Feb 06, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 02, 2025	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Oct 03, 2017	The V506I variant in the PKLR gene, also called PK Mallorca, has been reported previously in the heterozygous state with a second PKLR variant in a patient with PK deficiency (Pissard et al., 2006). The V506I variant was also identified in the heterozygous state in a child with concomitant hereditary spherocytosis and chronic hemolytic anemia who harbored V506I in trans with variants in hereditary spherocytosis genes; this individual's mother with V506I in the heterozygous state was asymptomatic (Zarza et al., 2000). The V506I variant is observed in 217/30782 (0.7%) alleles from individuals of South African background, including five homozygous individuals, in the ExAC dataset (Lek et al., 2016). The V506I variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position where amino acids with similar properties to Valine are tolerated across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. We interpret V506I as a variant of uncertain significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Nov 01, 2022	BP4_strong -
Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The PKLR p.Val475Ile variant was identified in 1 of 112 proband chromosomes (frequency: 0.0089) from individuals or families with pyruvate-kinase deficiency (Pissard_2006_PMID:16704447). The variant was also identified in the heterozygous state in a patient with partial red blood cell pyruvate-kinase deficiency concomitant hereditary spherocytosis and chronic hemolytic anemia; the patient's unaffected mother also carried the V475I variant (Zarza_2000_PMID:10702808). The variant was identified in dbSNP (ID: rs8177988), ClinVar (classified as a VUS by ARUP Laboratories, GeneDx, Fulgent Genetics and Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics) and LOVD 3.0 (classified as a VUS and pathogenic). The variant was identified in control databases in 1201 of 282864 chromosomes (5 homozygous) at a frequency of 0.004246 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: South Asian in 221 of 30616 chromosomes (freq: 0.007218), European (non-Finnish) in 769 of 129180 chromosomes (freq: 0.005953), Other in 37 of 7224 chromosomes (freq: 0.005122), Latino in 93 of 35436 chromosomes (freq: 0.002624), Ashkenazi Jewish in 21 of 10368 chromosomes (freq: 0.002025), European (Finnish) in 31 of 25120 chromosomes (freq: 0.001234) and African in 29 of 24966 chromosomes (freq: 0.001162); it was not observed in the East Asian population. The p.Val475 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and 3 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2025	PKLR: BS2 -

Pyruvate kinase deficiency of red cells

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre	Sep 22, 2024	- -
Likely benign, 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). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Pyruvate kinase deficiency of red cells;C1863224:Pyruvate kinase hyperactivity

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

PKLR-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 15, 2023

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.088

BayesDel_addAF

Benign

-0.096

BayesDel_noAF

Uncertain

0.090

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.64

D;.

Eigen

Benign

-0.25

Eigen_PC

Benign

-0.067

FATHMM_MKL

Uncertain

0.94

M_CAP

Benign

0.022

MetaRNN

Benign

0.011

T;T

MetaSVM

Uncertain

0.36

MutationAssessor

Benign

0.78

N;.

PrimateAI

Benign

0.33

PROVEAN

Benign

-0.34

N;N

REVEL

Uncertain

0.53

Sift

Benign

0.15

T;T

Sift4G

Benign

0.43

T;T

Polyphen

0.0

B;.

Vest4

0.098

MVP

0.79

MPC

0.34

ClinPred

0.0060

GERP RS

3.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.18

gMVP

0.77

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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