ClinVar Miner

Submissions for variant NM_000152.5(GAA):c.568C>T (p.Arg190Cys)

gnomAD frequency: 0.00001  dbSNP: rs771258854
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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 RCV000799395 SCV000939055 pathogenic Glycogen storage disease, type II 2023-11-06 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 190 of the GAA protein (p.Arg190Cys). This variant is present in population databases (rs771258854, gnomAD 0.006%). This missense change has been observed in individual(s) with Pompe disease (PMID: 29046207). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 645336). 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.Arg190 amino acid residue in GAA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 23000108, 29124014, 29149851). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Revvity Omics, Revvity RCV003141792 SCV003810589 uncertain significance not provided 2023-07-28 criteria provided, single submitter clinical testing
GeneDx RCV003141792 SCV005327225 likely pathogenic not provided 2023-10-06 criteria provided, single submitter clinical testing Observed with a second GAA variant in an individual with Pompe disease reported in the published literature, but it is not known whether the variants occurred on the same (in cis) or on different (in trans) chromosomes (PMID: 29046207); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 33560568, 19343043, 22253258, 29046207, 22644586, 23000108)

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