rs116100695

Positions:

chr1-155291918-G-A

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 12P and 1B. PM1PM5PP5_Very_StrongBP4

The NM_000298.6(PKLR):c.1456C>T(p.Arg486Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00295 in 1,613,440 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R486Q) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0028 ( 1 hom., cov: 31)

Exomes 𝑓: 0.0030 ( 7 hom. )

Consequence

PKLR
NM_000298.6 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:21

Conservation

PhyloP100: 1.78

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 11 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, 3 uncertain in NM_000298.6

PM5

Other missense variant is known to change same aminoacid residue: Variant chr1-155291917-C-A is described in Lovd as [Pathogenic].

PP5

Variant 1-155291918-G-A is Pathogenic according to our data. Variant chr1-155291918-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1513.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-155291918-G-A is described in UniProt as null. Variant chr1-155291918-G-A is described in Lovd as [Pathogenic]. Variant chr1-155291918-G-A is described in Lovd as [Pathogenic]. Variant chr1-155291918-G-A is described in Lovd as [Likely_pathogenic].

BP4

Computational evidence support a benign effect (MetaRNN=0.0360229). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PKLR	NM_000298.6 linkuse as main transcript	c.1456C>T	p.Arg486Trp	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.1456C>T	p.Arg486Trp	missense_variant	10/11	1	NM_000298.6	P3	P30613-1
PKLR	ENST00000392414.7 linkuse as main transcript	c.1363C>T	p.Arg455Trp	missense_variant	10/11	1		A1	P30613-2

Frequencies

GnomAD3 genomes

AF:

0.00277

AC:

421

AN:

152186

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000531

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00275

Gnomad ASJ

AF:

0.00144

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00455

Gnomad FIN

AF:

0.00913

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.00329

Gnomad OTH

AF:

0.00239

GnomAD3 exomes

AF:

0.00305

AC:

765

AN:

251132

Hom.:

AF XY:

0.00334

AC XY:

453

AN XY:

135782

show subpopulations

Gnomad AFR exome

AF:

0.000555

Gnomad AMR exome

AF:

0.00228

Gnomad ASJ exome

AF:

0.00278

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00369

Gnomad FIN exome

AF:

0.00841

Gnomad NFE exome

AF:

0.00296

Gnomad OTH exome

AF:

0.00294

GnomAD4 exome

AF:

0.00297

AC:

4345

AN:

1461136

Hom.:

Cov.:

AF XY:

0.00307

AC XY:

2231

AN XY:

726892

show subpopulations

Gnomad4 AFR exome

AF:

0.000568

Gnomad4 AMR exome

AF:

0.00228

Gnomad4 ASJ exome

AF:

0.00341

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00376

Gnomad4 FIN exome

AF:

0.00751

Gnomad4 NFE exome

AF:

0.00288

Gnomad4 OTH exome

AF:

0.00305

GnomAD4 genome

AF:

0.00276

AC:

421

AN:

152304

Hom.:

Cov.:

AF XY:

0.00308

AC XY:

229

AN XY:

74464

show subpopulations

Gnomad4 AFR

AF:

0.000529

Gnomad4 AMR

AF:

0.00274

Gnomad4 ASJ

AF:

0.00144

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00456

Gnomad4 FIN

AF:

0.00913

Gnomad4 NFE

AF:

0.00329

Gnomad4 OTH

AF:

0.00236

Alfa

AF:

0.00297

Hom.:

Bravo

AF:

0.00229

TwinsUK

AF:

0.00351

AC:

ALSPAC

AF:

0.00311

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00291

AC:

ExAC

AF:

0.00282

AC:

343

Asia WGS

AF:

0.00144

AC:

AN:

3478

EpiCase

AF:

0.00360

EpiControl

AF:

0.00344

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:21

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:9

Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 01, 2023	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 30681718, 29555771, 27871768, 32279356, 31980526, 29549173, 32165483, 11960989, 20981092, 8483951, 11054094, 24533562, 29349879, 29519373, 29519369, 11328279, 9827908, 18759866, 27346685, 29396846, 30358897, 28133914, 9482576, 32036089, 32543069, 32043619, 30609409, 31974203, 32974842, 26728349, 18708292, 33054133, 33054047, 23770304, 33054048, 34426522, 34662886, 33631127) -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 18, 2024	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 486 of the PKLR protein (p.Arg486Trp). This variant is present in population databases (rs116100695, gnomAD 0.8%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with pyruvate kinase deficiency (PMID: 9057665, 9657767, 9827908, 11054094, 17574881, 27871768, 32974842). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. This variant is commonly associated with mild to asymptomatic disease when observed in the homozygous state. However, this variant in conjunction with another pathogenic variant is a common cause of mild chronic hemolytic anemia, particularly in populations of southern Europe. Instances of moderate to severe disease in association with this variant have also been reported (PMID: 17360088, 9482576, 11328279, 10354117). ClinVar contains an entry for this variant (Variation ID: 1513). 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%. Experimental studies have shown that this variant moderately affects PKLR function (PMID: 11960989). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	May 24, 2023	PS4, PM1, PM3, PP4, PP5 -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2024	PKLR: PM3:Very Strong, PP4:Moderate, PM2:Supporting, PM5:Supporting, PS3:Supporting -
Likely pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 14, 2017	- -
Pathogenic, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The PKLR p.R486W variant was identified in over 30 individuals with pyruvate kinase deficiency and haemolytic anemia as a compound heterozygous variant; phenotypes ranged from mild to severe (Russo_2018_PMID:29396846; Jaouani_2017_PMID:28133914; Montllor_2016_PMID:27871768; Kedar_2009_PMID:18759866; Zanella_2001_PMID:11328279; Manco_2000_PMID:11054094; Zarza_1998_PMID:9827908; Baronciani_1993_PMID:8483951; Marcello_2008_PMID:18708292). The variant was identified in dbSNP (ID: rs116100695) and ClinVar (classified as pathogenic by Fulgent Genetics, ARUP Laboratories and Reproductive Health Research and Development, BGI Genomics, as likely pathogenic by Laboratory of Molecular Medicine, EGL Genetics and Knight Diagnostic Laboratories, Oregon Health and Services University, and as likely benign by Invitae). The variant was identified in control databases in 833 of 282498 chromosomes (2 homozygous) at a frequency of 0.002949 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: European (Finnish) in 204 of 25114 chromosomes (freq: 0.008123), South Asian in 113 of 30616 chromosomes (freq: 0.003691), European (non-Finnish) in 375 of 128890 chromosomes (freq: 0.002909), Other in 20 of 7218 chromosomes (freq: 0.002771), Ashkenazi Jewish in 28 of 10360 chromosomes (freq: 0.002703), Latino in 80 of 35424 chromosomes (freq: 0.002258) and African in 13 of 24926 chromosomes (freq: 0.000522), but was not observed in the East Asian population. Although the p.R486 residue is not conserved in mammals and other organisms, computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein. The variant occurs outside of the splicing consensus sequence and 1 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. Functional data suggests that this variant results in decreased catalytic efficiency (Valentini_2002_PMID:11960989). In summary, based on the above information this variant meets our laboratoryâ€šÃ„Ã´s criteria to be classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 20, 2023	The PKLR c.1456C>T; p.Arg486Trp variant (rs116100695), is reported in the literature as both a homozygous and compound heterozygous variant in several individuals affected with pyruvate kinase deficiency (Baronciani 1993, Kedar 2009, Manco 2000, Zanella 2001, Zarza 1998). This variant is reported in ClinVar (Variation ID: 1513). This variant is found in the general population with an overall allele frequency of 0.3% (833/282498 alleles, including two homozygotes) in the Genome Aggregation Database. Additionally, an alternative change at the same amino acid location (c.1457G>T, p.Arg486Leu) that is known to affect the PK activity has also been reported in an individual with hemolytic anemia (Pissard 2006). The arginine at codon 486 is moderately conserved and computational analyses predict that this variant is deleterious (REVEL 0.91). Based on available information, this variant is considered to be pathogenic. References: Baronciani L et al. Analysis of pyruvate kinase-deficiency mutations that produce nonspherocytic hemolytic anemia. Proc Natl Acad Sci U S A. 1993 90:4324-4327. Kedar P et al. Spectrum of novel mutations in the human PKLR gene in pyruvate kinase-deficient Indian patients with heterogeneous clinical phenotypes. Clin Genet. 2009 75:157-162. Manco L et al. A new PKLR gene mutation in the R-type promoter region affects the gene transcription causing pyruvate kinase deficiency. Br J Haematol. 2000 110:993-997. Pissard S et al. Pyruvate kinase deficiency in France: a 3-year study reveals 27 new mutations. Br J Haematol. 2006 133:683-689. Zanella A et al. Molecular characterization of the PK-LR gene in sixteen pyruvate kinase-deficient patients. Br J Haematol. 2001 113:43-48. Zarza R et al. Molecular characterization of the PK-LR gene in pyruvate kinase deficient Spanish patients. Red Cell Pathology Group of the Spanish Society of Haematology (AEHH). Br J Haematol. 1998 103:377-382. -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Nov 27, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Jul 31, 2024	- -

Pyruvate kinase deficiency of red cells

Pathogenic:8

Pathogenic, no assertion criteria provided	literature only	OMIM	Feb 01, 2009	- -
Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	Jan 24, 2023	The missense c.1456C>T (p.Arg486Trp) variant in PKLR gene has been reported previously (as the most common variant) in compound heterozygous state in multiple individuals affected with pyruvate kinase deficiency (Montllor et al. 2017; Jaouani et al. 2017; Canu et al. 2020). Experimental evidence shows that this variant is more thermoresistant than the wild type, did not induce significant conformational changes in the overall protein conformation, and leads to a drastic reduction in catalytic efficiency, which is consistent with a moderate phenotype (Valentini et al. 2002). The p.Arg486Trp variant is reported with an allele frequency of 0.3% in the gnomAD exomes database and is novel (not in any individuals) in 1000 Genomes database. This variant has been reported to the ClinVar database as Likely Pathogenic / Pathogenic (multiple submissions). The amino acid change p.Arg486Trp in PKLR is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Arg at position 486 is changed to a Trp changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Knight Diagnostic Laboratories, Oregon Health and Sciences University	Jan 27, 2016	The c.1456C>T (p.Arg486Trp) (NM_ 000298.5) missense variant has been reported in several unrelated individuals diagnosed with PK deficiency. These families have a well-documented clinical history of anemia (Zarza et al. 1998). Case-control studies have reported this variant as a common disease causing variant accounting for 9%-32% of diagnosed cases (Zarza et al., 1998; Zanella et al., 2001; Kedar et al., 2009). This variant has often been reported in trans with several pathogenic variants, and functional studies have shown that patients harboring this variant, in a compound heterozygous state, have reduced PK activity relative to normal controls (Zarza et al., 1998; Zanella et al., 2001; Valentini et al. 2002; Kedar et al., 2009). This c.1456C>T variant is reported at low frequency in the population databases (ESP = 0.291%; 1000 Genomes = 1%; ExAC = 0.298%), and multiple in silico algorithms predict this variant to have a deleterious effect (GERP = 4.85; CADD = 18.75; PolyPhen = 1; SIFT = 0). Therefore, this collective evidence supports the classification of the c.1456C>T (p.Arg486Trp) variant as a recessive Likely Pathogenic variant for PK deficiency. -
Likely pathogenic, criteria provided, single submitter	clinical testing	3billion	May 22, 2022	Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000001513). A different missense change at the same codon (p.Arg486Leu) has been reported to be associated with PKLR related disorder (PMID: 16704447). It is observed in the gnomAD v2.1.1 (https://gnomad.broadinstitute.org/) dataset at total allele frequency of 0.305%. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.91; 3Cnet: 0.83). Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Dec 23, 2021	The p.Arg486Trp variant in PKLR has been reported in >30 compound heterozygous individuals with pyruvate kinase deficiency and segregated in 1 affected relative (PKD; Baronciani 1993 PMID:8483951, Zarza 1998 PMID:9827908, Manco 2000 PMID:11054094, Zanella 2001 PMID:11328279, Kedar 2009 PMID:18759866, Kager 2016 PMID:26728349, Jaouani 2017 PMID:28133914, Canu 2020 PMID:32974842, Milanesio 2021, Jamwal 2020 PMIDL32036089). It has also been identified in 0.812% (204/25114) of Finnish (unknown frequency of PKD) and 0.29% (375/128890) of European chromosomes (1:20,000 frequency of PKD) by gnomAD (http://gnomad.broadinstitute.org). This variant has been reported in ClinVar (Variation ID 1513). Enzymatic studies suggest that the p.Arg486Trp variant may be a mild mutation with reduced activity (Zarza 1998 PMID:9827908, Zanella 2001 PMID:11328279, Valentini 2002 PMID:11960989, and Kedar 2009 PMID:18759866). In summary, although additional studies are required to fully establish its clinical significance, the p.Arg486Trp variant meets criteria to be classified as likely pathogenic for autosomal recessive pyruvate kinase deficiency. ACMG/AMP Criteria applied: PM3_VeryStrong, PS3_Moderate. -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, Heidelberg University	Sep 16, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Mar 29, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 10, 2023	Variant summary: PKLR c.1456C>T (p.Arg486Trp) results in a non-conservative amino acid change located in the Pyruvate Kinase C terminal domain (IPR015795) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.003 in 251132 control chromosomes in the gnomAD database, including 2 homozygotes. c.1456C>T has been reported in the literature in multiple homozygous and compound heterozygous individuals affected with moderate to severe Pyruvate Kinase Deficiency Of Red Cells (examples: Zanella_1997, Pastore_1998, Pissard_2006 ). These data indicate that the variant is very likely to be associated with disease. One publication reports experimental evidence that this variant moderately affects PKLR function (example: Valentini_2002). Fifteen submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Pyruvate kinase hyperactivity

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 04, 2022	- -
Pathogenic, no assertion criteria provided	curation	Reproductive Health Research and Development, BGI Genomics	Jan 06, 2020	NM_000298.5:c.1456C>T in the PKLR gene has an allele frequency of 0.008 in European (Finnish) subpopulation in the gnomAD database. This variant has been reported in multiple individuals with Pyruvate kinase deficiency, in a compound heterozygous state: 1190A>T/1456C>T, 1042-1044del/1456C>T, 992A>G/1456C>T, 1436G>A/1456C>T (PMID: 18759866); 1456C>T/1675C>T, 1456C>T/1010G>A, 1456C>T/1223C>T, 1456C>T/1070T>C, 1456C>T/721G>T(PMID: 9827908). Functional studies suggest that the p.Arg486Trp variant may be a mild mutation with reduced enzyme activity (PMID: 11960989).Taken together, we interprete this variant as Pathogenic/Likely pathogenic variant. ACMG/AMP Criteria applied: PM3_VeryStrong, PS3, PP4. -

See cases

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Nov 13, 2020

ACMG classification criteria: PS3, PS4, PM3, PP1, PP3, PP4, BS2 -

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

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

May 28, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.36

BayesDel_addAF

Pathogenic

0.16

BayesDel_noAF

Pathogenic

0.46

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.98

D;.

Eigen

Pathogenic

0.74

Eigen_PC

Uncertain

0.65

FATHMM_MKL

Uncertain

0.93

M_CAP

Uncertain

0.19

MetaRNN

Benign

0.036

T;T

MetaSVM

Pathogenic

1.0

MutationAssessor

Pathogenic

3.2

M;.

MutationTaster

Benign

1.0

A;A

PrimateAI

Benign

0.41

PROVEAN

Pathogenic

-6.0

D;D

REVEL

Pathogenic

0.91

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

1.0

D;.

Vest4

0.86

MVP

1.0

MPC

1.3

ClinPred

0.063

GERP RS

4.8

Varity_R

0.90

gMVP

0.93

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