VCV001429839.6 - ClinVar

NM_000289.6(PFKM):c.736C>T (p.Arg246Ter)

Germline

Classification

criteria provided, multiple submitters, no conflicts. Learn more about how ClinVar calculates review status.

Pathogenic/Likely pathogenic

2 out of 2 submissions contributed to this 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.

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000289.6(PFKM):c.736C>T (p.Arg246Ter)

Variation ID: 1429839 Accession: VCV001429839.6

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 12q13.11 12: 48134818 (GRCh38) [ NCBI UCSC ] 12: 48528601 (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 28, 2022	Feb 25, 2025	Aug 23, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_000289.6:c.736C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000280.1:p.Arg246Ter	nonsense
NM_001166686.2:c.949C>T	NP_001160158.1:p.Arg317Ter	nonsense
NM_001166687.2:c.736C>T	NP_001160159.1:p.Arg246Ter	nonsense
NM_001166688.2:c.736C>T	NP_001160160.1:p.Arg246Ter	nonsense
NM_001354735.1:c.1045C>T	NP_001341664.1:p.Arg349Ter	nonsense
NM_001354736.1:c.1045C>T	NP_001341665.1:p.Arg349Ter	nonsense
NM_001354737.1:c.949C>T	NP_001341666.1:p.Arg317Ter	nonsense
NM_001354738.1:c.949C>T	NP_001341667.1:p.Arg317Ter	nonsense
NM_001354739.1:c.949C>T	NP_001341668.1:p.Arg317Ter	nonsense
NM_001354740.1:c.880C>T	NP_001341669.1:p.Arg294Ter	nonsense
NM_001354741.2:c.760C>T	NP_001341670.1:p.Arg254Ter	nonsense
NM_001354742.2:c.736C>T	NP_001341671.1:p.Arg246Ter	nonsense
NM_001354743.2:c.736C>T	NP_001341672.1:p.Arg246Ter	nonsense
NM_001354744.2:c.736C>T	NP_001341673.1:p.Arg246Ter	nonsense
NM_001354745.2:c.649C>T	NP_001341674.1:p.Arg217Ter	nonsense
NM_001354746.2:c.736C>T	NP_001341675.1:p.Arg246Ter	nonsense
NM_001354747.2:c.586C>T	NP_001341676.1:p.Arg196Ter	nonsense
NM_001354748.2:c.586C>T	NP_001341677.1:p.Arg196Ter	nonsense
NM_001363619.2:c.736C>T	NP_001350548.1:p.Arg246Ter	nonsense
NR_148954.2:n.787C>T		non-coding transcript variant
NR_148955.1:n.1557C>T		non-coding transcript variant
NR_148956.2:n.713C>T		non-coding transcript variant
NR_148957.2:n.787C>T		non-coding transcript variant
NR_148958.2:n.787C>T		non-coding transcript variant
NR_148959.2:n.713C>T		non-coding transcript variant
NC_000012.12:g.48134818C>T
NC_000012.11:g.48528601C>T
NG_016199.2:g.34566C>T
LRG_1177:g.34566C>T
LRG_1177t1:c.736C>T	LRG_1177p1:p.Arg246Ter

... more HGVS ... less HGVS

Protein change

R217*, R246*, R254*, R317*, R196*, R294*, R349*

Other names

Canonical SPDI

NC_000012.12:48134817: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.

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

The Genome Aggregation Database (gnomAD), exomes 0.00000

Links

ClinGen: CA236511265 dbSNP: rs866904446 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.
PFKM		-	-	GRCh38 GRCh37	980	998

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.
Glycogen storage disease, type VII	Pathogenic/Likely pathogenic (2)	criteria provided, multiple submitters, no conflicts	Aug 23, 2023	RCV001939132.6

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 (Aug 23, 2023) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Glycogen storage disease, type VII Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV004203934.1 First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023
Pathogenic (Apr 14, 2023) C Contributing to aggregate classification	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Glycogen storage disease, type VII Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV002206892.4 First in ClinVar: Mar 28, 2022 Last updated: Feb 25, 2025	Publications: PubMed (2) PubMed: 7825568‚ 8037209 Comment: This variant is present in population databases (no rsID available, gnomAD 0.0009%). This sequence change creates a premature translational stop signal (p.Arg246) in the PFKM … (more) This variant is present in population databases (no rsID available, gnomAD 0.0009%). This sequence change creates a premature translational stop signal (p.Arg246) in the PFKM gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PFKM are known to be pathogenic (PMID: 7825568, 8037209). This variant has not been reported in the literature in individuals affected with PFKM-related conditions. ClinVar contains an entry for this variant (Variation ID: 1429839). For these reasons, this variant has been classified as Pathogenic. (less)

Comment:

This variant is present in population databases (no rsID available, gnomAD 0.0009%). This sequence change creates a premature translational stop signal (p.Arg246*) in the PFKM gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PFKM are known to be pathogenic (PMID: 7825568, 8037209). This variant has not been reported in the literature in individuals affected with PFKM-related conditions. ClinVar contains an entry for this variant (Variation ID: 1429839). For these reasons, this variant has been classified as Pathogenic.

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
Functional expression of human mutant phosphofructokinase in yeast: genetic defects in French Canadian and Swiss patients with phosphofructokinase deficiency.	Raben N	American journal of human genetics	1995	PMID: 7825568
Common mutations in the phosphofructokinase-M gene in Ashkenazi Jewish patients with glycogenesis VII--and their population frequency.	Sherman JB	American journal of human genetics	1994	PMID: 8037209

Text-mined citations for rs866904446 ...

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 Feb 26, 2025

ClinVar Genomic variation as it relates to human health

NM_000289.6(PFKM):c.736C>T (p.Arg246Ter)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs866904446 ...