1-155291858-C-T

Variant names:

• chr1-155291858-C-T
• rs8177988
• NM_000298.6:c.1516G>A

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 3P and 9B. PM1 PP2 BP4_Strong BP6 BS2

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. 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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7 B:4
• Conservation: PhyloP100: 3.97
• Publications: 16 publications found

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 Gene-Disease associations (from GenCC):

• pyruvate kinase deficiency of red cells

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), Orphanet
• pyruvate kinase hyperactivity

  Inheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• PM1: In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_000298.6
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 45 curated pathogenic missense variants (we use a threshold of 10). The gene has 0 curated benign missense variants. Gene score misZ: 0.98056 (below the threshold of 3.09). Trascript score misZ: 1.5963 (below the threshold of 3.09). GenCC associations: The gene is linked to pyruvate kinase deficiency of red cells, pyruvate kinase hyperactivity.
• BP4: Computational evidence support a benign effect (MetaRNN=0.010544926).
• BP6: Variant 1-155291858-C-T is Benign according to our data. Variant chr1-155291858-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 235407.
• BS2: High Homozygotes in GnomAd4 at 2 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000298.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PKLR	NM_000298.6	MANE Select	c.1516G>A	p.Val506Ile	missense	Exon 10 of 11	NP_000289.1
	PKLR	NM_181871.4		c.1423G>A	p.Val475Ile	missense	Exon 10 of 11	NP_870986.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PKLR	ENST00000342741.6	TSL:1 MANE Select	c.1516G>A	p.Val506Ile	missense	Exon 10 of 11	ENSP00000339933.4
	PKLR	ENST00000392414.7	TSL:1	c.1423G>A	p.Val475Ile	missense	Exon 10 of 11	ENSP00000376214.3

Frequencies

GnomAD3 genomes AF: 0.00413 AC: 629 AN: 152136 Hom.: 2 Cov.: 31

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

GnomAD2 exomes AF: 0.00436 AC: 1096 AN: 251476 AF XY: 0.00493

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 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.: 41 Cov.: 33 AF XY: 0.00561 AC XY: 4083 AN XY: 727196

African (AFR) AF: 0.000986 AC: 33 AN: 33478

American (AMR) AF: 0.00271 AC: 121 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00134 AC: 35 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00681 AC: 587 AN: 86250

European-Finnish (FIN) AF: 0.00140 AC: 75 AN: 53420

Middle Eastern (MID) AF: 0.00558 AC: 32 AN: 5732

European-Non Finnish (NFE) AF: 0.00636 AC: 7075 AN: 1111966

Other (OTH) AF: 0.00392 AC: 237 AN: 60386

GnomAD4 genome AF: 0.00413 AC: 629 AN: 152254 Hom.: 2 Cov.: 31 AF XY: 0.00394 AC XY: 293 AN XY: 74442

African (AFR) AF: 0.00108 AC: 45 AN: 41558

American (AMR) AF: 0.00536 AC: 82 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 4 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00499 AC: 24 AN: 4814

European-Finnish (FIN) AF: 0.00132 AC: 14 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00653 AC: 444 AN: 68010

Other (OTH) AF: 0.00757 AC: 16 AN: 2114

Alfa AF: 0.00545 Hom.: 5

Bravo AF: 0.00434

TwinsUK AF: 0.00674 AC: 25

ALSPAC AF: 0.00519 AC: 20

ESP6500AA AF: 0.00159 AC: 7

ESP6500EA AF: 0.00512 AC: 44

ExAC AF: 0.00419 AC: 509

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00676

EpiControl AF: 0.00747

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:7 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:5 Benign:2

Mar 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PKLR: BS2

Nov 01, 2022

Mayo Clinic Laboratories, Mayo Clinic

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

BP4_strong

Feb 06, 2015

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jun 12, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Oct 03, 2017

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

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.

Pyruvate kinase deficiency of red cells Uncertain:1 Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Likely benign

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). 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.

Sep 22, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Pyruvate kinase deficiency of red cells;C1863224:Pyruvate kinase hyperactivity Uncertain:1

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PKLR-related disorder Benign:1

Feb 15, 2023

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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 v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	-0.096	T
BayesDel_noAF	Uncertain	0.090
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.64	D
Eigen	Benign	-0.25
Eigen_PC	Benign	-0.067
FATHMM_MKL	Uncertain	0.94	D
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.011	T
MetaSVM	Uncertain	0.36	D
MutationAssessor	Benign	0.78	N
PhyloP100		4.0
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.34	N
REVEL	Uncertain	0.53
Sift	Benign	0.15	T
Sift4G	Benign	0.43	T
Polyphen		0.0	B
Vest4		0.098
MVP		0.79
MPC		0.34
ClinPred		0.0060	T
GERP RS		3.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.18
gMVP		0.77
Mutation Taster		=75/25	polymorphism

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

Other links and lift over

dbSNP: rs8177988; hg19: chr1-155261649; COSMIC: COSV99048047; COSMIC: COSV99048047;