VCV000816680.12 - ClinVar

NM_000298.6(PKLR):c.1082A>C (p.Asn361Thr)

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.

(4)

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
Likely pathogenic(2); Uncertain significance(2)

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.1082A>C (p.Asn361Thr)

Variation ID: 816680 Accession: VCV000816680.12

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 1q22 1: 155294269 (GRCh38) [ NCBI UCSC ] 1: 155264060 (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	Mar 8, 2020	Feb 4, 2024	Apr 6, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_000298.6:c.1082A>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000289.1:p.Asn361Thr	missense
NM_000298.5:c.1082A>C
NM_181871.4:c.989A>C	NP_870986.1:p.Asn330Thr	missense
NC_000001.11:g.155294269T>G
NC_000001.10:g.155264060T>G
NG_011677.1:g.12166A>C
LRG_1136:g.12166A>C
LRG_1136t1:c.1082A>C	LRG_1136p1:p.Asn361Thr

... more HGVS ... less HGVS

Protein change

N330T, N361T

Other names

Canonical SPDI

NC_000001.11:155294268:T:G

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.

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

The Genome Aggregation Database (gnomAD) 0.00001

Trans-Omics for Precision Medicine (TOPMed) 0.00002

Links

dbSNP: rs1358047518 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.
Pyruvate kinase deficiency of red cells	Likely pathogenic (1)	criteria provided, single submitter	Nov 22, 2019	RCV001007616.9
not provided	Conflicting interpretations of pathogenicity (3)	criteria provided, conflicting classifications	Apr 6, 2023	RCV001811621.18

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.
Likely pathogenic (Nov 22, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Pyruvate kinase deficiency of red cells Affected status: unknown Allele origin: germline	Johns Hopkins Genomics, Johns Hopkins University Accession: SCV001167303.1 First in ClinVar: Mar 08, 2020 Last updated: Mar 08, 2020	Comment: This PKLR variant is absent from large population datasets and has not been reported in the literature, to our knowledge. Three bioinformatic tools queried predict … (more) This PKLR variant is absent from large population datasets and has not been reported in the literature, to our knowledge. Three bioinformatic tools queried predict that this substitution would be possibly damaging, and the asparagine residue at this position is evolutionarily conserved across the vertebrates assessed. This asparagine is located at the A/C subunit interface of the protein where other amino acid subsitutions have been reported in patients with hemolytic anemia due to pyruvate kinase deficiency. A different subsitution at this amino acid residue (p.Asn361Asp) has been identified in two patients with pyruvate kinase deficiency who each had a different second PKLR missense variant. We consider PKLR c.1082A>C to be likely pathogenic. (less)
Likely pathogenic (Mar 15, 2022)	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2021) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories Accession: SCV002048272.3 First in ClinVar: Jan 08, 2022 Last updated: Mar 04, 2023	Comment: The PKLR c.1082A>C; p.Asn361Thr variant (rs1358047518), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 816680). An … (more) The PKLR c.1082A>C; p.Asn361Thr variant (rs1358047518), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 816680). An alternative change at this codon (p.Asn361Asp) has been reported in a compound heterozygous configuration with additional PKLR variants in one individual with PK deficiency (Lenzner 1994). This variant is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. The Asparagine at codon 361 is highly conserved, and computational analyses predict this variant is deleterious (REVEL: 0.906). Based on available information, this variant is considered to be likely pathogenic. (less)
Uncertain significance (Aug 15, 2022)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV003805138.1 First in ClinVar: Mar 04, 2023 Last updated: Mar 04, 2023	Comment: Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; … (more) Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge (less)
Uncertain significance (Apr 06, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV003808469.2 First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024

Comment:

This PKLR variant is absent from large population datasets and has not been reported in the literature, to our knowledge. Three bioinformatic tools queried predict that this substitution would be possibly damaging, and the asparagine residue at this position is evolutionarily conserved across the vertebrates assessed. This asparagine is located at the A/C subunit interface of the protein where other amino acid subsitutions have been reported in patients with hemolytic anemia due to pyruvate kinase deficiency. A different subsitution at this amino acid residue (p.Asn361Asp) has been identified in two patients with pyruvate kinase deficiency who each had a different second PKLR missense variant. We consider PKLR c.1082A>C to be likely pathogenic.

Comment:

The PKLR c.1082A>C; p.Asn361Thr variant (rs1358047518), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 816680). An alternative change at this codon (p.Asn361Asp) has been reported in a compound heterozygous configuration with additional PKLR variants in one individual with PK deficiency (Lenzner 1994). This variant is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. The Asparagine at codon 361 is highly conserved, and computational analyses predict this variant is deleterious (REVEL: 0.906). Based on available information, this variant is considered to be likely pathogenic.

Comment:

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge

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

There are no citations for germline classification of this variant in ClinVar. If you know of citations for this variation, please consider submitting that information to ClinVar.

Text-mined citations for rs1358047518 ...

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.1082A>C (p.Asn361Thr)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs1358047518 ...