PKLR p.Gly111Arg

Variant names:

• chr1-155295709-C-G
• NM_000298.6:c.331G>C
• PKLR p.Gly111Arg

Your query was ambiguous. Multiple possible variants found:

• chr1-155295709-C-G
• chr1-155295709-C-T
• chr1-155295707-CCC-ACG
• chr1-155295707-CCC-GCG
• chr1-155295707-CCC-TCG
• chr1-155295707-CCC-TCT

Variant summary

Our verdict is Pathogenic. The variant received 15 ACMG points: 15P and 0B. PS1_Very_Strong PM2 PP2 PP3_Strong

The NM_000298.6(PKLR):​c.331G>C​(p.Gly111Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 14/22 in silico tools predict a damaging outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PKLR NM_000298.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.77
• Publications: 0 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: Laboratory for Molecular Medicine, Orphanet, Labcorp Genetics (formerly Invitae), ClinGen
• pyruvate kinase hyperactivity

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

ACMG classification

Our verdict: Pathogenic. The variant received 15 ACMG points.

• PS1: Transcript NM_000298.6 (PKLR) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.
• PM2: Very rare variant in population databases, with high coverage
• 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: MetaRNN computational evidence supports a deleterious effect, 0.991

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.331G>C	p.Gly111Arg	missense	Exon 3 of 11	NP_000289.1	P30613-1
	PKLR	NM_181871.4		c.238G>C	p.Gly80Arg	missense	Exon 3 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.331G>C	p.Gly111Arg	missense	Exon 3 of 11	ENSP00000339933.4	P30613-1
	PKLR	ENST00000392414.7	TSL:1	c.238G>C	p.Gly80Arg	missense	Exon 3 of 11	ENSP00000376214.3	P30613-2
	PKLR	ENST00000434082.3	TSL:5	c.139G>C	p.Gly47Arg	missense	Exon 3 of 5	ENSP00000398037.3	F8W6W2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	1.0	D
Eigen	Pathogenic	0.97
Eigen_PC	Pathogenic	0.84
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.57	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	0.90	D
MutationAssessor	Pathogenic	3.9	H
PhyloP100		7.8
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-7.4	D
REVEL	Pathogenic	0.97
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.023	D
Varity_R		0.98
gMVP		0.95
Mutation Taster		=1/99	disease causing

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

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

Other links and lift over

hg19: chr1-155265500;