ClinVar Miner

Submissions for variant NM_000292.3(PHKA2):c.535G>A (p.Ala179Thr)

gnomAD frequency: 0.00001  dbSNP: rs749441642
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV001940036 SCV002179828 uncertain significance Glycogen storage disease IXa1 2023-12-25 criteria provided, single submitter clinical testing This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 179 of the PHKA2 protein (p.Ala179Thr). This variant is present in population databases (rs749441642, gnomAD 0.005%). This missense change has been observed in individual(s) with clinical features of glycogen storage disease type IXa (PMID: 25070466). ClinVar contains an entry for this variant (Variation ID: 1410251). 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 disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV002222743 SCV002500422 uncertain significance not specified 2022-03-16 criteria provided, single submitter clinical testing Variant summary: PHKA2 c.535G>A (p.Ala179Thr) results in a non-conservative amino acid change located in the GH15-like domain (IPR011613) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 5.5e-06 in 183455 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.535G>A has been reported in the literature in at least one individual affected with glycogen storage disease type IXa (Brown_2015). The report does not provide unequivocal conclusions about association of the variant with Glycogen Phosphorylase Kinase Deficiency. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as uncertain significance.
GeneDx RCV003320856 SCV004025426 uncertain significance not provided 2023-02-11 criteria provided, single submitter clinical testing In silico analysis supports that this missense variant does not alter protein structure/function; Observed in large population cohorts, and one individual was reported as hemizygous (gnomAD; internal data); This variant is associated with the following publications: (PMID: 25070466)

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