ClinVar Miner

Submissions for variant NM_000152.5(GAA):c.2296T>A (p.Tyr766Asn)

gnomAD frequency: 0.00001  dbSNP: rs941181575
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV001302690 SCV001491908 likely pathogenic Glycogen storage disease, type II 2024-03-25 criteria provided, single submitter clinical testing This sequence change replaces tyrosine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 766 of the GAA protein (p.Tyr766Asn). This variant is present in population databases (no rsID available, gnomAD 0.002%). This missense change has been observed on the same chromosome as p.Pro522Ser in individual(s) with Pompe disease (PMID: 31086307). ClinVar contains an entry for this variant (Variation ID: 1005758). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt GAA protein function with a positive predictive value of 95%. This variant disrupts the p.Tyr766 amino acid residue in GAA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 22521436, 22538254, 28394184). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Fulgent Genetics, Fulgent Genetics RCV001302690 SCV002780902 pathogenic Glycogen storage disease, type II 2022-03-23 criteria provided, single submitter clinical testing
Revvity Omics, Revvity RCV003145534 SCV003828514 uncertain significance not provided 2023-01-10 criteria provided, single submitter clinical testing
GeneDx RCV003145534 SCV005370750 likely pathogenic not provided 2024-03-27 criteria provided, single submitter clinical testing Has been reported in the published literature in a patient with known diagnosis of Pompe disease in cis with p.M427I and as well as [p.(P522S; Y766N)] on the opposite allele (in trans) (PMID: 31086307); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 22521436, 26693141, 31086307)

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