ClinVar Miner

Submissions for variant NM_000152.5(GAA):c.2188G>T (p.Glu730Ter) (rs1555601828)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Integrated Genetics/Laboratory Corporation of America RCV000586591 SCV000695649 pathogenic Glycogen storage disease, type II 2016-06-29 criteria provided, single submitter clinical testing Variant summary: The GAA c.2188G>T (p.Glu730X) variant results in a premature termination codon, predicted to cause a truncated or absent GAA protein due to nonsense mediated decay, which are commonly known mechanisms for disease. If this nonsense variant results in a protein product, this variant is not predicted to truncate any known functional domains of Lysosomal alpha-glucosidase. However, two independent functional assays in COS-1 and HEK 293 T cells have shown that the activity of Glu730X is not significantly different from mock control (Ebrahim_JIMD_2012 and Pittis_Am J Med Genet A_2003). Neither of these studies confirmed protein expression via Western Blotting, thus it is uncertain if this variant results in a stable protein that is inactive, nonsense mediated decay, or an unstable protein. At least one frameshift variant downstream of this position has been classified as pathogenic by our laboratory (e.g. p.Lys849fsX38), and one in silico tool predicts a damaging outcome for this variant. Additionally, this variant was absent in 39208 control chromosomes, and was cited in compound heterozygous state in one patient in the literature with Infantile Onset Pompe Disease. Taken together, this variant is classified as Pathogenic.

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