VCV000767707.24 - ClinVar

NM_000298.6(PKLR):c.829G>A (p.Glu277Lys)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(7)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Conflicting classifications of pathogenicity
Uncertain significance(4); Likely benign(1)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000298.6(PKLR):c.829G>A (p.Glu277Lys)

Variation ID: 767707 Accession: VCV000767707.24

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 1q22 1: 155294618 (GRCh38) [ NCBI UCSC ] 1: 155264409 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Dec 17, 2019	Oct 8, 2024	Dec 12, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_000298.6:c.829G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000289.1:p.Glu277Lys	missense
NM_181871.4:c.736G>A	NP_870986.1:p.Glu246Lys	missense
NC_000001.11:g.155294618C>T
NC_000001.10:g.155264409C>T
NG_011677.1:g.11817G>A
LRG_1136:g.11817G>A
LRG_1136t1:c.829G>A	LRG_1136p1:p.Glu277Lys

... more HGVS ... less HGVS

Protein change

E246K, E277K

Other names

Canonical SPDI

NC_000001.11:155294617:C:T

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

0.00260 (T)

Allele frequency Help The frequency of the allele represented by this VCV record.

The Genome Aggregation Database (gnomAD), exomes 0.00069

Exome Aggregation Consortium (ExAC) 0.00075

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00238

1000 Genomes Project 0.00260

The Genome Aggregation Database (gnomAD) 0.00269

1000 Genomes Project 30x 0.00312

Trans-Omics for Precision Medicine (TOPMed) 0.00317

Links

dbSNP: rs147689373 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
PKLR		-	-	GRCh38 GRCh38 GRCh37	310	337

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
not provided	Conflicting interpretations of pathogenicity (5)	criteria provided, conflicting classifications	Dec 12, 2023	RCV000946502.27
Pyruvate kinase deficiency of red cells	Uncertain significance (1)	criteria provided, single submitter	Apr 27, 2017	RCV001097711.12
PKLR-related disorder	Benign (1)	no assertion criteria provided	Aug 29, 2019	RCV003970661.2

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Uncertain significance (Apr 27, 2017)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Pyruvate kinase deficiency of red cells Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV001254014.1 First in ClinVar: May 31, 2020 Last updated: May 31, 2020	Publications: PubMed (2) PubMed: 21833022‚ 23082140 Comment: 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, … (more) 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). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. (less)
Uncertain significance (Mar 01, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Not provided Affected status: unknown Allele origin: germline	Mayo Clinic Laboratories, Mayo Clinic Accession: SCV001715316.2 First in ClinVar: Jun 15, 2021 Last updated: Jan 26, 2024	Publications: PubMed (4) PubMed: 11960989‚ 15982340‚ 21833022‚ 23082140 Number of individuals with the variant: 9
Uncertain significance (Jul 10, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV003808481.2 First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024
Likely benign (Dec 12, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV001092644.2 First in ClinVar: Dec 17, 2019 Last updated: Feb 20, 2024
Uncertain significance (Nov 03, 2023)	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2024) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories Accession: SCV001159263.3 First in ClinVar: Feb 10, 2020 Last updated: Feb 20, 2024
Uncertain significance (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: unknown	Department of Pathology and Laboratory Medicine, Sinai Health System Additional submitter: Franklin by Genoox Study: The Canadian Open Genetics Repository (COGR) Accession: SCV001551809.1 First in ClinVar: Apr 13, 2021 Last updated: Apr 13, 2021	Comment: The PKLR p.Glu246Lys variant was not identified in the literature nor was it identified in ClinVar, Cosmic, or LOVD 3.0. The variant was identified in … (more) The PKLR p.Glu246Lys variant was not identified in the literature nor was it identified in ClinVar, Cosmic, or LOVD 3.0. The variant was identified in dbSNP (ID: rs147689373) and in control databases in 242 of 282216 chromosomes (2 homozygous) at a frequency of 0.000857 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: African in 215 of 24902 chromosomes (freq: 0.008634), Latino in 21 of 35410 chromosomes (freq: 0.0005931), Other in 2 of 7200 chromosomes (freq: 0.0002778), South Asian in 3 of 30598 chromosomes (freq: 0.00009805) and European (non-Finnish) in 1 of 128714 chromosomes (freq: 0.000007769), while the variant was not observed in the Ashkenazi Jewish, European (Finnish) or East Asian populations. The p.Glu246 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and 3 of 4 in silico or computational prediction software programs (SpliceSiteFinder, NNSPLICE, 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. (less)
Benign (Aug 29, 2019)	no assertion criteria provided Method: clinical testing	PKLR-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV004784068.2 First in ClinVar: Mar 16, 2024 Last updated: Oct 08, 2024	Comment: This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).

Comment:

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). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

Comment:

The PKLR p.Glu246Lys variant was not identified in the literature nor was it identified in ClinVar, Cosmic, or LOVD 3.0. The variant was identified in dbSNP (ID: rs147689373) and in control databases in 242 of 282216 chromosomes (2 homozygous) at a frequency of 0.000857 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: African in 215 of 24902 chromosomes (freq: 0.008634), Latino in 21 of 35410 chromosomes (freq: 0.0005931), Other in 2 of 7200 chromosomes (freq: 0.0002778), South Asian in 3 of 30598 chromosomes (freq: 0.00009805) and European (non-Finnish) in 1 of 128714 chromosomes (freq: 0.000007769), while the variant was not observed in the Ashkenazi Jewish, European (Finnish) or East Asian populations. The p.Glu246 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and 3 of 4 in silico or computational prediction software programs (SpliceSiteFinder, NNSPLICE, 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.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Pyruvate kinase deficiency in sub-Saharan Africa: identification of a highly frequent missense mutation (G829A;Glu277Lys) and association with malaria.	Machado P	PloS one	2012	PMID: 23082140
Genetic diversity in human erythrocyte pyruvate kinase.	Berghout J	Genes and immunity	2012	PMID: 21833022
Red cell pyruvate kinase deficiency: molecular and clinical aspects.	Zanella A	British journal of haematology	2005	PMID: 15982340
Structure and function of human erythrocyte pyruvate kinase. Molecular basis of nonspherocytic hemolytic anemia.	Valentini G	The Journal of biological chemistry	2002	PMID: 11960989

Text-mined citations for rs147689373 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Oct 27, 2024

ClinVar Genomic variation as it relates to human health

NM_000298.6(PKLR):c.829G>A (p.Glu277Lys)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs147689373 ...