dbSNP rs116100695: PKLR:p.Arg486Trp (chr1-155291918-G-A) – ACMG Classification: Pathogenic (14 pts)

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 16P and 2B. PS3PM1PP2PP3PP5_Very_StrongBP4BS2_Supporting

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 (★★). ClinVar reports functional evidence for this variant: "SCV000223943: "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" and additional evidence is available in ClinVar. 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:29

Conservation

PhyloP100: 1.78

Publications

64 publications found

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 Gene-Disease associations (from GenCC):

pyruvate kinase deficiency of red cells
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Laboratory for Molecular Medicine, Orphanet, Labcorp Genetics (formerly Invitae), ClinGen
pyruvate kinase hyperactivity
Inheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

PKLR links:

Genome browser will be placed here

new If you want to explore the variant's impact on the transcript NM_000298.6, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 14 ACMG points.

PS3

PS3 evidence extracted from ClinVar submissions: SCV000223943: "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)."; SCV000713497: Enzymatic studies suggest that the p.Arg486Trw 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).; SCV004171978: Experimental studies have shown that this variant moderately affects PKLR function (Valentini et al., 2002).; SCV004223638: One publication reports experimental evidence that this variant moderately affects PKLR function (example: Valentini_2002).; SCV005415943: "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product."; SCV000885966: Structural and functional analysis of the variant protein show a moderate decrease in the catalytic efficiency (Valentini 2002). PMID: 11960989; SCV001035168: Experimental studies have shown that this variant moderately affects PKLR function (PMID: 11960989).; SCV001550687: Functional data suggests that this variant results in decreased catalytic efficiency (Valentini_2002_PMID:11960989).; SCV001142310: Functional studies suggest that the p.Arg486Trp variant may be a mild mutation with reduced enzyme activity (PMID: 11960989).; SCV005344843: Functional studies indicate this variant disrupts protein function (Valentini et al. 2002. PubMed ID: 11960989).

PM1

In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 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 hyperactivity, pyruvate kinase deficiency of red cells.

PP3

Multiple lines of computational evidence support a deleterious effect 8: BayesDel_addAF, BayesDel_noAF, Cadd, Eigen, MutationAssessor, PROVEAN, REVEL, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster, phyloP100way_vertebrate, PrimateAI was below the threshold]

PP5

Variant 1-155291918-G-A is Pathogenic according to our data. Variant chr1-155291918-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 1513.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP4

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

BS2

High Homozygotes in GnomAdExome4 at 7 AD,AR geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PKLR	NM_000298.6	MANE Select	c.1456C>T	p.Arg486Trp	missense	Exon 10 of 11	NP_000289.1	P30613-1
	PKLR	NM_181871.4		c.1363C>T	p.Arg455Trp	missense	Exon 10 of 11	NP_870986.1	P30613-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PKLR	ENST00000342741.6	TSL:1 MANE Select	c.1456C>T	p.Arg486Trp	missense	Exon 10 of 11	ENSP00000339933.4	P30613-1
	PKLR	ENST00000392414.7	TSL:1	c.1363C>T	p.Arg455Trp	missense	Exon 10 of 11	ENSP00000376214.3	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

GnomAD2 exomes

AF:

0.00305

AC:

765

AN:

251132

AF XY:

0.00334

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 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

African (AFR)

AF:

0.000568

AC:

AN:

33452

American (AMR)

AF:

0.00228

AC:

102

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.00341

AC:

AN:

26136

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39700

South Asian (SAS)

AF:

0.00376

AC:

324

AN:

86222

European-Finnish (FIN)

AF:

0.00751

AC:

401

AN:

53418

Middle Eastern (MID)

AF:

0.00539

AC:

AN:

5194

European-Non Finnish (NFE)

AF:

0.00288

AC:

3197

AN:

1111978

Other (OTH)

AF:

0.00305

AC:

184

AN:

60318

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

232

464

696

928

1160

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

120

240

360

480

600

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00276

AC:

421

AN:

152304

Hom.:

Cov.:

AF XY:

0.00308

AC XY:

229

AN XY:

74464

show subpopulations

African (AFR)

AF:

0.000529

AC:

AN:

41566

American (AMR)

AF:

0.00274

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00144

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00456

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00913

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.0136

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00329

AC:

224

AN:

68006

Other (OTH)

AF:

0.00236

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.511

Heterozygous variant carriers

123

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00292

Hom.:

Bravo

AF:

0.00229

Asia WGS

AF:

0.00144

AC:

AN:

3478

EpiCase

AF:

0.00360

EpiControl

AF:

0.00344

ClinVar

ClinVar submissions

Significance:Pathogenic/Likely pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Pyruvate kinase deficiency of red cells (14)

not provided (10)

Pyruvate kinase hyperactivity (2)

PKLR-related disorder (1)

Pyruvate kinase deficiency of red cells;C1863224:Pyruvate kinase hyperactivity (1)

See cases (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.36

BayesDel_addAF

Pathogenic

0.16

BayesDel_noAF

Pathogenic

0.46

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.98

Eigen

Pathogenic

0.74

Eigen_PC

Uncertain

0.65

FATHMM_MKL

Uncertain

0.93

M_CAP

Uncertain

0.19

MetaRNN

Benign

0.036

MetaSVM

Pathogenic

1.0

MutationAssessor

Pathogenic

3.2

PhyloP100

1.8

PrimateAI

Benign

0.41

PROVEAN

Pathogenic

-6.0

REVEL

Pathogenic

0.91

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Varity_R

0.90

gMVP

0.93

Mutation Taster

=51/49

disease causing (ClinVar)

(source)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over