ClinVar Miner

Submissions for variant NM_000289.6(PFKM):c.1127G>A (p.Arg376Gln)

gnomAD frequency: 0.00001  dbSNP: rs187131358
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000670080 SCV000794896 uncertain significance Glycogen storage disease, type VII 2017-10-18 criteria provided, single submitter clinical testing
Invitae RCV000670080 SCV001588492 pathogenic Glycogen storage disease, type VII 2023-11-22 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 376 of the PFKM protein (p.Arg376Gln). RNA analysis indicates that this missense change induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs187131358, gnomAD 0.006%). This missense change has been observed in individual(s) with glycogen storage disease (PMID: 8659544). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 554445). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this missense change results in activation of a cryptic splice site within intron 12 and introduces a premature termination codon (PMID: 8659544). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000670080 SCV002103442 pathogenic Glycogen storage disease, type VII 2022-02-08 criteria provided, single submitter clinical testing Variant summary: PFKM c.1127G>A (p.Arg376Gln) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. As the variant alters the last conserved nucleotide of exon 12 adjacent to the canonical intron 12 splicing donor site, several computational tools predict a significant impact on normal splicing: Three predict the variant abolishes the canonical 5' splicing donor site. One predict the variant weakens the canonical 5' splicing donor site. At least one publication reports experimental evidence that this variant affects mRNA splicing leading to the retention of 155 nucleotides of the intronic sequence (example, Nichols_1996). This is predicted to result in premature termination of translation. The variant allele was found at a frequency of 1.2e-05 in 251252 control chromosomes. c.1127G>A has been reported in the literature as a compound heterozygous genotype in four individuals affected with Glycogen Storage Disease, Type VII (Tarui disease) in a Swedish family (example, Nichols_1996). These data indicate that the variant is likely to be associated with disease. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as pathogenic and one laboratory classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics RCV000670080 SCV004203939 likely pathogenic Glycogen storage disease, type VII 2023-06-06 criteria provided, single submitter clinical testing

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