ClinVar Genomic variation as it relates to human health
NM_000289.6(PFKM):c.2003del (p.Pro668fs)
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.
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.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000289.6(PFKM):c.2003del (p.Pro668fs)
Variation ID: 632192 Accession: VCV000632192.24
- Type and length
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Deletion, 1 bp
- Location
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Cytogenetic: 12q13.11 12: 48145039 (GRCh38) [ NCBI UCSC ] 12: 48538822 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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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 May 10, 2014 Feb 14, 2024 Dec 21, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000289.6:c.2003del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000280.1:p.Pro668fs frameshift NM_000289.6:c.2003delC MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NM_000289.5:c.2003del NM_001166686.2:c.2216del NP_001160158.1:p.Pro739fs frameshift NM_001166687.2:c.2003del NP_001160159.1:p.Pro668fs frameshift NM_001166688.2:c.2003del NP_001160160.1:p.Pro668fs frameshift NM_001354735.1:c.2312del NP_001341664.1:p.Pro771fs frameshift NM_001354736.1:c.2312del NP_001341665.1:p.Pro771fs frameshift NM_001354737.1:c.2216del NP_001341666.1:p.Pro739fs frameshift NM_001354738.1:c.2216del NP_001341667.1:p.Pro739fs frameshift NM_001354739.1:c.2216del NP_001341668.1:p.Pro739fs frameshift NM_001354740.1:c.2147del NP_001341669.1:p.Pro716fs frameshift NM_001354741.2:c.2027del NP_001341670.1:p.Pro676fs frameshift NM_001354742.2:c.2003del NP_001341671.1:p.Pro668fs frameshift NM_001354743.2:c.2003del NP_001341672.1:p.Pro668fs frameshift NM_001354744.2:c.2003del NP_001341673.1:p.Pro668fs frameshift NM_001354745.2:c.1916del NP_001341674.1:p.Pro639fs frameshift NM_001354746.2:c.1877del NP_001341675.1:p.Pro626fs frameshift NM_001354747.2:c.1853del NP_001341676.1:p.Pro618fs frameshift NM_001354748.2:c.1853del NP_001341677.1:p.Pro618fs frameshift NM_001363619.2:c.1910del NP_001350548.1:p.Pro637fs frameshift NR_148954.2:n.2306del non-coding transcript variant NR_148955.1:n.3076del non-coding transcript variant NR_148956.2:n.2232del non-coding transcript variant NR_148957.2:n.2461del non-coding transcript variant NR_148958.2:n.2209del non-coding transcript variant NR_148959.2:n.2135del non-coding transcript variant NC_000012.12:g.48145041del NC_000012.11:g.48538824del NG_016199.2:g.44789del LRG_1177:g.44789del LRG_1177t1:c.2003del LRG_1177p1:p.Pro668fs - Protein change
- P618fs, P676fs, P626fs, P739fs, P637fs, P639fs, P668fs, P716fs, P771fs
- Other names
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- Canonical SPDI
- NC_000012.12:48145038:CCC:CC
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe 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.
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Allele frequency
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The frequency of the allele represented by this VCV record.
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- Comment on variant
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 | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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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
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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. |
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PFKM | - | - |
GRCh38 GRCh37 |
915 | 932 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic (7) |
criteria provided, multiple submitters, no conflicts
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Dec 21, 2023 | RCV000779105.20 | |
Pathogenic (1) |
criteria provided, single submitter
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Jul 17, 2018 | RCV000826149.4 | |
Pathogenic (1) |
criteria provided, single submitter
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Jun 1, 2022 | RCV002464314.1 |
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
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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
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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. |
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Pathogenic
(Dec 11, 2018)
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criteria provided, single submitter
Method: clinical testing
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Glycogen storage disease, type VII
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV000915597.1
First in ClinVar: May 27, 2019 Last updated: May 27, 2019 |
Comment:
The PFKM c.2003delC (p.Pro668GlnfsTer17) variant results in a frameshift and is predicted to result in premature termination of the protein. The p.Pro668GlnfsTer17 variant has been … (more)
The PFKM c.2003delC (p.Pro668GlnfsTer17) variant results in a frameshift and is predicted to result in premature termination of the protein. The p.Pro668GlnfsTer17 variant has been reported in at least seven individuals of Ashkenazi Jewish descent with glycogen storage disease type VII, also referred to as PFK deficiency. The variant was observed in a homozygous state in two individuals and in a compound heterozygous state in five individuals, which includes one set of siblings and one father-son pair (Sherman et al. 1994; Vorgerd et al. 1996). In one family, affected siblings were both compound heterozygous for the p.Pro668GlnfsTer17 variant and a splice donor variant. Their unaffected father carried the splice donor variant and their unaffected mother and sister carried the p.Pro668GlnfsTer17 variant. This variant was absent from 250 Ashkenazi Jewish controls but is reported at a frequency of 0.00276 in the Ashkenazi Jewish population from the Genome Aggregation Database. In erythrocytes from individuals carrying the p.Pro668GlnfsTer17 variant, PFK enzyme activity was shown to be reduced by approximately 50% compared to wild type. Based on the potential impact of frameshift variants and evidence from the literature, the p.Pro668GlnfsTer17 variant is classified as pathogenic for glycogen storage disease type VII. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. (less)
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Pathogenic
(Jul 17, 2018)
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criteria provided, single submitter
Method: clinical testing
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Glycogen storage disease
(Autosomal recessive inheritance)
Affected status: not provided
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000967680.1
First in ClinVar: Aug 26, 2019 Last updated: Aug 26, 2019 |
Comment:
The p.Pro739GlnfsX17 variant in PFKM has been reported in 5 Ashkenazi Jewish ind ividuals with glycogen storage disease type 7 in the homozygous or compound … (more)
The p.Pro739GlnfsX17 variant in PFKM has been reported in 5 Ashkenazi Jewish ind ividuals with glycogen storage disease type 7 in the homozygous or compound hete rozygous state and segregated with the disease in 2 affected relatives from 2 fa milies (Sherman 1994, Vorgerd 1996, Ristow 1997). This variant has been identifi ed in 0.3% (28/10150) of Ashkenazi Jewish chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs767095759). Although this variant has been seen in the general population, its frequency is not high enough to rule out a pathogenic role. In vitro studies provide some evidence th at the p.Pro739GlnfsX17 variant may impact protein function (Vorgerd 1996, Risto w 1997); however, these types of assays may not accurately represent biological function. This variant is predicted to cause a frameshift, which alters the prot ein?s amino acid sequence beginning at position 739 and leads to a premature ter mination codon 17 amino acids downstream. This alteration is then predicted to l ead to a truncated or absent protein. In summary, this variant meets criteria to be classified as pathogenic for glycogen storage disease type 7 in an autosomal recessive manner based upon presence in affected individuals, functional eviden ce, and predicted impact on protein. ACMG/AMP Criteria applied: PVS1_Strong; PM3 _Strong; PP1; PS3_Supporting (less)
Number of individuals with the variant: 1
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Pathogenic
(Dec 03, 2020)
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criteria provided, single submitter
Method: clinical testing
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Glycogen storage disease, type VII
Affected status: unknown
Allele origin:
germline
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ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV002048264.1
First in ClinVar: Jan 08, 2022 Last updated: Jan 08, 2022 |
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Pathogenic
(Jun 01, 2022)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV002758925.1
First in ClinVar: Dec 11, 2022 Last updated: Dec 11, 2022 |
Comment:
Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of … (more)
Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 8037209) (less)
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Pathogenic
(Oct 23, 2023)
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criteria provided, single submitter
Method: clinical testing
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Glycogen storage disease, type VII
Affected status: unknown
Allele origin:
unknown
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Baylor Genetics
Accession: SCV004203928.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Pathogenic
(May 18, 2023)
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criteria provided, single submitter
Method: clinical testing
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Glycogen storage disease, type VII
Affected status: unknown
Allele origin:
germline
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Revvity Omics, Revvity
Accession: SCV004237851.1
First in ClinVar: Feb 04, 2024 Last updated: Feb 04, 2024 |
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Pathogenic
(Dec 21, 2023)
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criteria provided, single submitter
Method: clinical testing
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Glycogen storage disease, type VII
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000945851.6
First in ClinVar: Aug 13, 2019 Last updated: Feb 14, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Pro668Glnfs*17) in the PFKM gene. It is expected to result in an absent or disrupted protein … (more)
This sequence change creates a premature translational stop signal (p.Pro668Glnfs*17) 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 is present in population databases (rs767095759, gnomAD 0.3%). This premature translational stop signal has been observed in individuals with phosphofructokinase (PFK) deficiency and PFK deficiency (PMID: 8037209). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 632192). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Dec 01, 1997)
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no assertion criteria provided
Method: literature only
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GLYCOGEN STORAGE DISEASE VII
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000021369.2
First in ClinVar: Apr 04, 2013 Last updated: May 10, 2014 |
Comment on evidence:
In Ashkenazi Jewish patients with GSD VII (GSD7; 232800), Sherman et al. (1994) identified a 1-bp deletion (2003delC) in exon 22 of the PFKM gene, … (more)
In Ashkenazi Jewish patients with GSD VII (GSD7; 232800), Sherman et al. (1994) identified a 1-bp deletion (2003delC) in exon 22 of the PFKM gene, resulting in a frameshift and a truncated PFKM protein with 16 altered amino acids at the C terminus. Two patients were homozygous for the mutation and 2 were compound heterozygous for the deletion and another pathogenic mutation. Ristow et al. (1997) identified the 1-bp deletion in compound heterozygosity with the common exon 5 deletion (610681.0005) in an Ashkenazi Jewish father and son with GSD VII. The family had previously been reported by Vorgerd et al. (1996) and was unusual because 2 members in subsequent generations were affected. (less)
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Pathogenic
(Sep 16, 2020)
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no assertion criteria provided
Method: clinical testing
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Glycogen storage disease type VII
Affected status: unknown
Allele origin:
germline
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Natera, Inc.
Accession: SCV001458713.1
First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021 |
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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. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Deficiency of phosphofructo-1-kinase/muscle subtype in humans impairs insulin secretion and causes insulin resistance. | Ristow M | The Journal of clinical investigation | 1997 | PMID: 9389749 |
Muscle phosphofructokinase deficiency in two generations. | Vorgerd M | Journal of the neurological sciences | 1996 | PMID: 8880699 |
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 rs767095759 ...
HelpRecord last updated Mar 17, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.
ClinGen staff contributed the HGVS expression for this variant.