ClinVar Genomic variation as it relates to human health

The p.R190H variant (also known as c.569G>A), located in coding exon 2 of the GAA gene, results from a G to A substitution at nucleotide position 569. The arginine at codon 190 is replaced by histidine, an amino acid with highly similar properties. This variant has been reported in individuals with Pompe disease who were compound heterozygous with additional alterations in GAA (Kroos M et al. Hum Mutat, 2008 Jun;29:E13-26; Bali DS et al. Muscle Nerve, 2011 May;43:665-70; Er TK et al. Clin Chim Acta, 2014 Feb;429:18-25; Johnson K et al. Orphanet J Rare Dis, 2017 Nov;12:173; Fukuhara Y et al. Mol Genet Metab Rep, 2018 Mar;14:3-9). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.

The p.Arg190His variant in GAA has been reported in 2 Dutch and 1 Taiwanese individuals with Glycogen Storage Disease II, segregated with disease in 2 affected siblings from 1 family (PMID: 23000108, 24444888), and has also been reported likely pathogenic by Counsyl and pathogenic by Integrated Genetics in ClinVar (Variation ID: 188809). This variant has been identified in 0.006% (1/16218) of African chromosomes, 0.006% (2/34578) of Latino chromosomes, and 0.001% (1/113436) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs528367092). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. In vitro functional studies provide some evidence that the p.Arg190His variant may impact GAA activity and proteolytically activated GAA levels (PMID: 22644586). However, these types of assays may not accurately represent biological function. 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 species (scarlet macaw) carries a Histidine (His) at this position, raising the possibility that this change at this position may be tolerated. However, the presence of this variant in combination with pathogenic and likely pathogenic variants and in individuals with Glycogen Storage Disease II increases the likelihood that the p.Arg190His variant is pathogenic (PMID: 23000108, 24444888). The phenotype of 3 individuals heterozygous for this variant is highly specific for Glycogen Storage Disease II based on abnormally low GAA activity assay results in fibroblasts or a dried blood spot (PMID: 23000108, 24444888). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PS3, PP3, PM2, PP4, PM3_Supporting (Richards 2015).

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 190 of the GAA protein (p.Arg190His). This variant is present in population databases (rs528367092, gnomAD 0.007%). This missense change has been observed in individual(s) with Pompe disease (PMID: 21484825, 23000108, 24444888, 29149851, 31076647). ClinVar contains an entry for this variant (Variation ID: 188809). 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 observed in individuals with GAA-related conditions (PMID: 29046207), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.

Variant summary: GAA c.569G>A (p.Arg190His) results in a non-conservative amino acid change located in the Galactose mutarotase, N-terminal barrel of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was observed with an allele frequency of 1.6e-05 in 244686 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in GAA causing Glycogen Storage Disease, Type 2 (Pompe Disease) (1.6e-05 vs 0.0042), allowing no conclusion about variant significance. The variant, c.569G>A, has been reported in the literature in multiple individuals affected with Glycogen Storage Disease, Type 2 (Pompe Disease). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic.

Published functional studies suggest that R190H results in reduced enzyme activity (PMID: 22644586); 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: 18425781, 29149851, 24444888, 21484825, 23000108, 29124014, 34426522, 32528171, 19343043, 22253258, 31076647, 22644586)