ClinVar Genomic variation as it relates to human health

PM2, PM5, PP3, PP4

The p.Arg375His variant in GAA has been reported in two Asian individuals with glycogen storage disease II (PMID: 21757382, 21484825), and has been reported in 0.02% of African chromosomes, 0.01% (3/30544) of South Asian chromosomes, and 0.0008% (1/127354) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs142752477). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported in ClinVar as a VUS by Invitae (VariationID: 572725). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. One additional likely pathogenic variant, resulting in a different amino acid change at the same position, p.Arg375Leu, has been reported in association with the disease in the literature and ClinVar (PMID: 25103075, 18429042, 18429042; VariationID: 283230). The phenotype of a heterozygous individual is highly specific for Glycogen Storage Disease II based on GAA activity assays with fibroblast cells (PMID: 21757382). In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PM5_supporting, PM2, PP3, PP4 (Richards 2015).

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 375 of the GAA protein (p.Arg375His). This variant is present in population databases (rs142752477, gnomAD 0.02%). This missense change has been observed in individual(s) with Pompe disease (PMID: 21484825, 21757382; Invitae). 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: 572725). 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.Arg375 amino acid residue in GAA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 18429042, 22990675, 24158270, 29422078). 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.

Previously reported in association with late-onset GSDII (PMID: 21757382, 33202836, 21484825); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Enzyme activity analysis confirmed a patient harboring p.(R375H) and an additional GAA variant had less than 1% GAA enzyme activity (PMID: 21484825); Located in the critical Catalytic (/)8 Barrel Domain (PMID: 19343043, 22253258); This variant is associated with the following publications: (PMID: 30275481, 33202836, 21757382, 21484825, 19343043, 22253258)