ClinVar Miner

Submissions for variant NM_000152.5(GAA):c.2237G>C (p.Trp746Ser) (rs752921215)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Genomic Research Center, Shahid Beheshti University of Medical Sciences RCV000626060 SCV000746682 likely pathogenic Glycogen storage disease, type II 2017-12-18 criteria provided, single submitter clinical testing
Counsyl RCV000626060 SCV000795205 likely pathogenic Glycogen storage disease, type II 2017-11-08 criteria provided, single submitter clinical testing
Invitae RCV000626060 SCV000950050 pathogenic Glycogen storage disease, type II 2018-12-20 criteria provided, single submitter clinical testing This sequence change replaces tryptophan with serine at codon 746 of the GAA protein (p.Trp746Ser). The tryptophan residue is highly conserved and there is a large physicochemical difference between tryptophan and serine. This variant is present in population databases (rs752921215, ExAC 0.04%). This variant has been observed in several individuals affected with Pompe disease (PMID: 22081099, 18425781). ClinVar contains an entry for this variant (Variation ID: 188484). Experimental studies have shown that this missense change causes a mild disruption of GAA protein function (PMID: 23430493). This variant disrupts the p.Trp746 amino acid residue in GAA. Other variant(s) that disrupt this residue have been observed in affected individuals (PMID: 18458862, 21757382, 21232767, 23430493, 25526786, 27099502, 25093132), suggesting that it is a clinically significant residue. As a result, variants that disrupt this residue are likely to be causative of disease. For these reasons, this variant has been classified as Pathogenic.
Broad Institute Rare Disease Group,Broad Institute RCV000626060 SCV001422665 pathogenic Glycogen storage disease, type II 2020-01-22 no assertion criteria provided curation The p.Trp746Ser variant in GAA has been reported in 1 Danish, 1 Chinese, 1 Northern European, and 6 Italian individuals with Glycogen Storage Disease II (PMID: 28490439, 24169249, 18425781, 22081099), and has been identified in 0.032% (8/24924) of African chromosomes and 0.011% (4/35424) of Latino chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs752921215). 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 pathogenic variant by Invitae and a likely pathogenic variant by Counsyl and Shahid Beheshti University of Medical Sciences in ClinVar (Variation ID: 188484). In vitro functional studies provide some evidence that the p.Trp746Ser variant may impact GAA activity (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. The presence of this variant in combination with a reported pathogenic variant in 6 individuals with Glycogen Storage Disease II increases the likelihood that the p.Trp746Ser variant is pathogenic (PMID: 22081099). The phenotype of 2 individuals heterozygous for this variant is highly specific for Glycogen Storage Disease II based on reduced GAA activity in muscle tissue, consistent with disease (PMID: 22081099). Four additional variants (p.Trp746Cys, p.Trp746Gly, p.Trp746Arg, and p.Trp746Leu) at the the same position, including a reported pathogenic variant, have been reported in association with disease in ClinVar, supporting that a change at this position may not be tolerated (Variation ID: 265160, 556431, 499293, 284776). In summary, this variant meets criteria to be classified as pathogenic for Glycogen Storage Disease II in an autosomal recessive manner based on occurrences with a pathogenic GAA variant in individuals with Glycogen Storage Disease II and functional evidence. ACMG/AMP Criteria applied: PS3, PM5, PM3_supporting, PM2, PP3, PP4 (Richards 2015).

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