NM_000298.6(PKLR):c.993C>A (p.Asp331Glu) AND not provided

Germline classification:: Pathogenic/Likely pathogenic (4 submissions)
Last evaluated:: Nov 21, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV001508883.10

Allele description [Variation Report for NM_000298.6(PKLR):c.993C>A (p.Asp331Glu)]

NM_000298.6(PKLR):c.993C>A (p.Asp331Glu)

Gene:

PKLR:pyruvate kinase L/R [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

1q22

Genomic location:

Preferred name:

NM_000298.6(PKLR):c.993C>A (p.Asp331Glu)

HGVS:

NC_000001.11:g.155294358G>T
NG_011677.1:g.12077C>A
NM_000298.6:c.993C>AMANE SELECT
NM_181871.4:c.900C>A
NP_000289.1:p.Asp331Glu
NP_870986.1:p.Asp300Glu
LRG_1136t1:c.993C>A
LRG_1136:g.12077C>A
LRG_1136p1:p.Asp331Glu
NC_000001.10:g.155264149G>T
NM_000298.5:c.993C>A
p.Asp331Glu

Protein change:

D300E

Links:

dbSNP: rs138476691

NCBI 1000 Genomes Browser:

rs138476691

Molecular consequence:

NM_000298.6:c.993C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_181871.4:c.900C>A - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

Recent activity

Clear Turn Off Turn On

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

Help

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001715314	Mayo Clinic Laboratories, Mayo Clinic	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Aug 4, 2020)	germline	clinical testing	PubMed (9) [See all records that cite these PMIDs] 26087744, 7706479, 26832193, 9160692, 29519373, 32266426, 11960989, 15982340, 25741868
SCV002024657	Revvity Omics, Revvity	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jul 18, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004252954	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Nov 21, 2023)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 7706479, 9657767, 10354117, 17360088, 29519373, 28492532
SCV004563944	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2024)	Likely pathogenic (Sep 14, 2023)	germline	clinical testing	Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	1	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Erythrocyte pyruvate kinase deficiency: 2015 status report.

Grace RF, Zanella A, Neufeld EJ, Morton DH, Eber S, Yaish H, Glader B.

Am J Hematol. 2015 Sep;90(9):825-30. doi: 10.1002/ajh.24088. Epub 2015 Aug 14. Review.

PubMed [citation]

PMID:: 26087744
PMCID:: PMC5053227

Red blood cell PK deficiency: An update of PK-LR gene mutation database.

Canu G, De Bonis M, Minucci A, Capoluongo E.

Blood Cells Mol Dis. 2016 Mar;57:100-9. doi: 10.1016/j.bcmd.2015.12.009. Epub 2016 Jan 12. Review.

PubMed [citation]

PMID:: 26832193

See all PubMed Citations (13)

Details of each submission

From Mayo Clinic Laboratories, Mayo Clinic, SCV001715314.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (9)

Description

PM1, PM2_supporting, PM3, PP3

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		1	not provided	not provided	not provided

From Revvity Omics, Revvity, SCV002024657.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Invitae, SCV004252954.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

This sequence change replaces aspartic acid, which is acidic and polar, with glutamic acid, which is acidic and polar, at codon 331 of the PKLR protein (p.Asp331Glu). This variant is present in population databases (rs138476691, gnomAD 0.03%). This missense change has been observed in individual(s) with pyruvate kinase deficiency (PMID: 7706479, 9657767, 10354117, 17360088, 29519373). ClinVar contains an entry for this variant (Variation ID: 1163643). 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%. For these reasons, this variant has been classified as Pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories, SCV004563944.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

The PKLR c.993C>A; p.Asp331Glu variant (rs138476691) is reported in the literature in two individuals affected with PK deficiency (Baronciani 1995, Svidnicki 2018). This variant is also reported in ClinVar (Variation ID: 1163643). This variant is found in the general population with an overall allele frequency of 0.008% (24/282626 alleles) in the Genome Aggregation Database. Computational analyses predict that this variant is deleterious (REVEL: 0.942). Additionally, other variants at this codon (c.992A>G, p.Asp331Gly; c.991G>A, p.Asp331Asn) have been reported in individuals with PK deficiency and are considered disease causing (Baronciani 1998, Gupta 2007, Jamwal 2020). Based on available information, this variant is considered to be likely pathogenic. REFERENCES Baronciani L et al. Molecular study of pyruvate kinase deficient patients with hereditary nonspherocytic hemolytic anemia. J Clin Invest. 1995 Apr. PMID: 7706479 Baronciani L et al. Hematologically important mutations: red cell pyruvate kinase (2nd update). Blood Cells Mol Dis. 1998 Sep. PMID: 10087985 Gupta N et al. Prenatal diagnosis for a novel homozygous mutation in PKLR gene in an Indian family. Prenat Diagn. 2007 Feb. PMID: 17191259 Jamwal M et al. Next-Generation Sequencing-Based Diagnosis of Unexplained Inherited Hemolytic Anemias Reveals Wide Genetic and Phenotypic Heterogeneity. J Mol Diagn. 2020 Apr. PMID: 32036089 Svidnicki M et al. Novel mutations associated with pyruvate kinase deficiency in Brazil. Rev Bras Hematol Hemoter. 2018 Jan - Mar. PMID: 29519373

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Mar 16, 2024

ClinVar

Relating variation to medicine