ClinVar Miner

Submissions for variant NM_000152.5(GAA):c.365del (p.Met122fs) (rs786204661)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000169456 SCV000220881 likely pathogenic Glycogen storage disease, type II 2014-11-13 criteria provided, single submitter literature only
Invitae RCV000169456 SCV001380433 pathogenic Glycogen storage disease, type II 2020-06-19 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Met122Argfs*20) in the GAA gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been observed in combination with another GAA variant in an individual affected with severe, later onset Pompe disease (PMID: 20638881). ClinVar contains an entry for this variant (Variation ID: 189059). Loss-of-function variants in GAA are known to be pathogenic (PMID: 18425781, 22252923). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000169456 SCV001437364 pathogenic Glycogen storage disease, type II 2020-09-25 criteria provided, single submitter clinical testing Variant summary: GAA c.365delT (p.Met122ArgfsX20) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 247798 control chromosomes (gnomAD v2). c.365delT has been reported in the literature in a compound heterozygous individual who was affected with the late onset form of Glycogen Storage Disease, Type 2 (Pompe Disease), where the other variant found in trans was the common disease variant, c.-32-13T>G, that is associated with the late-onset form of the disorder (Bernstein_2010). This publication also reported that the enzyme activity measured in patient derived cultured fibroblasts was about 5-7% of the normal (Bernstein_2010). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014, and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

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