ClinVar Miner

Submissions for variant NM_000289.6(PFKM):c.238-3A>G

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Revvity Omics, Revvity RCV003134804 SCV003814884 uncertain significance Glycogen storage disease, type VII 2022-11-08 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV003134804 SCV003928917 likely pathogenic Glycogen storage disease, type VII 2023-04-24 criteria provided, single submitter clinical testing Variant summary: PFKM c.238-3A>G alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: three predict the variant abolishes a 3' acceptor site, and four predict the variant creates a 3' acceptor site 2 nucleotides upstream, potentially leading to a frameshift. At least one publication reports experimental evidence that this variant affects mRNA splicing, leading to an insertion of two nucleotides, which is predicted to result in a frameshift and a premature termination codon (p.G80fs4X; Musumeci_2012), which confirms the computational predictions. The variant allele was found at a frequency of 4.1e-06 in 242486 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. The variant, c.238-3A>G, has been reported in the literature in at least one homozygous individual affected with Glycogen Storage Disease, Type VII (Musumeci_2012). Authors of this study also reported an enzymatic activity ~1% of normal, in muscle biopsy sample taken from the homozygous patient (Musumeci_2012). One ClinVar submitter (evaluation after 2014) has cited the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Baylor Genetics RCV003134804 SCV004203951 likely pathogenic Glycogen storage disease, type VII 2023-03-05 criteria provided, single submitter clinical testing
Invitae RCV003134804 SCV004295018 likely pathogenic Glycogen storage disease, type VII 2024-01-12 criteria provided, single submitter clinical testing This sequence change falls in intron 4 of the PFKM gene. It does not directly change the encoded amino acid sequence of the PFKM protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (no rsID available, gnomAD 0.0009%). This variant has been observed in individual(s) with glycogen storage disease type VII (PMID: 22133655). ClinVar contains an entry for this variant (Variation ID: 2434666). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in AG insertion, predicting a frameshift and introduces a premature termination codon (PMID: 22133655). The resulting mRNA is expected to undergo nonsense-mediated decay. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

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