ClinVar Miner

Submissions for variant NM_000152.5(GAA):c.2242dup (p.Glu748fs) (rs777275355)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000411023 SCV000486019 likely pathogenic Glycogen storage disease, type II 2016-03-15 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000524025 SCV000706065 pathogenic not provided 2017-01-31 criteria provided, single submitter clinical testing
GeneDx RCV000524025 SCV000617645 pathogenic not provided 2018-09-12 criteria provided, single submitter clinical testing The c.2242dupG pathogenic variant in the GAA gene has been previously reported in multiple individuals with Pompe Disease (Beesley et al., 1998; Montalvo et al., 2006; Bali et al., 2011). One individual harboring the c.2242dupG variant, as well as an additional GAA variant, was found to have <1% of normal GAA activity (Bali et al., 2011). The c.2242dupG variant causes a frameshift starting with codon Glutamic Acid 748, changes this amino acid to a Glycine residue, and creates a premature Stop codon at position 48 of the new reading frame, denoted p.Glu748GlyfsX48. This variant is predicted to cause loss of normal protein function through protein truncation or nonsense-mediated mRNA decay. The c.2242dupG variant is not observed in large population cohorts (Lek et al., 2016). In summary, we interpret c.2242dupG to be a pathogenic variant.
Invitae RCV000411023 SCV000959782 pathogenic Glycogen storage disease, type II 2018-11-13 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Glu748Glyfs*48) in the GAA gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs777275355, ExAC 0.003%). This variant has been observed in combination with another GAA variant in several individuals affected with glycogen storage disease type II (PMID: 9535769, 16917947, 21484825, 29122469). This variant is also known as insGnt2243 and insG2242 in the literature. ClinVar contains an entry for this variant (Variation ID: 370651). Loss-of-function variants in GAA are known to be pathogenic (PMID: 18425781, 22252923). For these reasons, this variant has been classified as Pathogenic.

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