Submissions for variant NM_000152.5(GAA):c.1781G>C (p.Arg594Pro)

dbSNP: rs775450536

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel	RCV001248974	SCV002817449	likely pathogenic	Glycogen storage disease, type II	2022-11-15	reviewed by expert panel	curation	The NM_000152.5:c.1781G>C variant in GAA is a missense variant predicted to cause substitution of arginine by proline at amino acid 594 (p.Arg594Pro). This variant has been detected in at least 3 probands with Pompe disease (PMID: 34952985, 19588081, 18425781, clinical diagnostic laboratory). Two of these individuals are reported to have clinical features consistent with the condition, and one is reported to be on enzyme replacement therapy, but residual GAA activity was not provided (PMID: 19588081, 34952985). Another patient, identified by a clinical diagnostic laboratory, has deficiency GAA activity in dried blood spot and a brother reported to have Pompe disease (PP4_Moderate). Each of the 3 probands is compound heterozygous, phase unknown, for the variant and another pathogenic variant in GAA, either c.525delT (clinical diagnostic laboratory), c.32‐13T>G (PMID: 34952985) or c.1941C>G (p.Cys647Trp) (PMID: 19588081) (PM3). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00002 (2/111938 alleles) in the European (non-Finnish) population, which is lower than the ClinGen LSD VCEP’s threshold for PM2_Supporting (<0.001), meeting this criterion (PM2_Supporting). Expression of the variant in COS cells resulted in 1.2% wild type GAA activity leading the variant to be described as Class B (“potentially less severe”), indicating that this variant may impact protein function (PMID: 22644586) (PS3_Moderate). The computational predictor REVEL gives a score of 0.941 which is above the threshold of 0.7, evidence that correlates with impact to GAA function (PP3). Another missense change (c.1781G>T, p.Arg594His) at the same amino acid residue has been classified as likely pathogenic by the ClinGen LSD VCEP (PM5_Suppporting). There is a ClinVar entry for this variant (Variation ID: 289361, 1 star review status) with one submitter classifying the variant as pathogenic, 3 as likely pathogenic, and one as uncertain significance. In summary, this variant meets the criteria to be classified as likely pathogenic for Pompe disease based on the GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Storage Disorders Variant Curation Expert panel (Specifications Version 2.0): PM3, PS3_Moderate, PP4_Moderate, PP3, PM2_Supporting, PM5_Supporting.
Eurofins Ntd Llc (ga)	RCV000375289	SCV000343710	uncertain significance	not provided	2016-07-08	criteria provided, single submitter	clinical testing
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV001248974	SCV001422807	likely pathogenic	Glycogen storage disease, type II	2020-01-22	criteria provided, single submitter	curation	The heterozygous p.Arg594Pro variant in GAA has been reported in 2 Brazilian and 1 northern European individuals with Glycogen Storage Disease II and segregated with disease in 2 affected siblings from 1 family (PMID: 19588081, 18425781). This variant has been identified in 0.002% (2/111938) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs775450536). 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 as a VUS by EGL in ClinVar (Variation ID: 289361). In vitro functional studies provide some evidence that the p.Arg594Pro variant may reduce proteolytically activated GAA protein levels and impact protein function (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. This variant was reported in combination with a likely pathogenic variant and in individuals with Glycogen Storage Disease II (PMID: 19588081). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PS3, PM2, PP3 (Richards 2015).
Invitae	RCV001248974	SCV001577048	likely pathogenic	Glycogen storage disease, type II	2020-07-16	criteria provided, single submitter	clinical testing	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. This variant disrupts the p.Arg594 amino acid residue in GAA. Other variant(s) that disrupt this residue have been observed in individuals with GAA-related conditions (PMID: 29451150), which suggests that this may be a clinically significant amino acid residue. This variant has been reported to affect GAA protein function (PMID: 22644586). This variant has been observed in individual(s) with Pompe disease (PMID: 19588081, 30564623). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 289361). This variant is present in population databases (rs775450536, ExAC 0.003%). This sequence change replaces arginine with proline at codon 594 of the GAA protein (p.Arg594Pro). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and proline.
Genome-Nilou Lab	RCV001248974	SCV001810625	likely pathogenic	Glycogen storage disease, type II	2021-07-22	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000375289	SCV002069653	pathogenic	not provided	2020-11-20	criteria provided, single submitter	clinical testing	The c.1781G>C sequence change in exon 13 results in the amino acid change p.Arg594Pro. This sequence change has been described in the gnomAD database in two individuals with a low overall population frequency of 0.0008% (dbSNP rs775450536). The p.Arg594Pro change affects a highly conserved amino acid residue located in a domain of the GAA protein that is known to be functional. The p.Arg594Pro substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). This sequence change has been reported in three individuals with Glycogen storage disease II, two of whom were siblings and were also found to carry another pathogenic sequence change in the GAA gene, c.1941C>G. Additionally, two other sequence changes at the same location, p.Arg594His and p.Arg594Cys, have been reported in individuals with Glycogen storage disease II (PMIDs: 22644586, 29451150). Functional studies have demonstrated that the p.Arg594Pro change may reduce GAA protein function (PMID: 2264586). The p.Arg594Pro change has previously been reported with the p.Glu176Argfs*45 change in an individual with late-onset limb-girdle muscular dystrophy, however the cis/trans configuration was not reported (PMID: 30564623).