ClinVar Miner

Submissions for variant NM_000289.6(PFKM):c.2003del (p.Pro668fs) (rs767095759)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Clinical Services Laboratory,Illumina RCV000779105 SCV000915597 pathogenic Glycogen storage disease, type VII 2018-12-11 criteria provided, single submitter clinical testing 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.
Invitae RCV000779105 SCV000945851 pathogenic Glycogen storage disease, type VII 2018-07-30 criteria provided, single submitter clinical testing 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. This variant is present in population databases (rs767095759, ExAC 0.02%). This variant has been observed in several individuals affected with  phosphofructokinase (PFK) deficiency and has been observed to segregate with PFK deficiency in a family (PMID: 8037209). This variant is also known as c.2079delC in the literature. Loss-of-function variants in PFKM are known to be pathogenic (PMID: 7825568, 8037209). For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000826149 SCV000967680 pathogenic Glycogen storage disease 2018-07-17 criteria provided, single submitter clinical testing 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
OMIM RCV000779105 SCV000021369 pathogenic Glycogen storage disease, type VII 1997-12-01 no assertion criteria provided literature only

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