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

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Revvity Omics, Revvity	RCV003134804	SCV003814884	likely pathogenic	Glycogen storage disease, type VII	2022-10-01	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
Labcorp Genetics (formerly Invitae), Labcorp	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.