ClinVar Miner

Submissions for variant NM_000152.5(GAA):c.307T>G (p.Cys103Gly) (rs398123174)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000078179 SCV000227028 pathogenic not provided 2012-11-14 criteria provided, single submitter clinical testing
GeneDx RCV000078179 SCV000322396 pathogenic not provided 2018-07-03 criteria provided, single submitter clinical testing The C103G variant in the GAA gene has been reported previously in multiple unrelated individuals with Pompe disease (Hermans et al., 2004; Joshi et al., 2008; Pittis et al., 2008). The C103G variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). The C103G variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. In vitro expression analysis of C103G indicates that this variant leads to approximately 98% loss of lysosomal alpha glucosidase activity (Hermans et al., 2004). We interpret C103G as a pathogenic variant.
Invitae RCV000811478 SCV000951746 pathogenic Glycogen storage disease, type II 2020-07-21 criteria provided, single submitter clinical testing This sequence change replaces cysteine with glycine at codon 103 of the GAA protein (p.Cys103Gly). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and glycine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in combination with another GAA variant in several individuals affected with glycogen storage disease type II (PMID: 21109266, 29181627, 18429042, 18607768, 14695532, 24158270). ClinVar contains an entry for this variant (Variation ID: 92483). This variant has been reported to affect GAA protein function (PMID: 14695532). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000811478 SCV001361271 pathogenic Glycogen storage disease, type II 2019-05-06 criteria provided, single submitter clinical testing Variant summary: GAA c.307T>G (p.Cys103Gly) results in a non-conservative amino acid change located in the P-type trefoil domain (IPR000519) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 248096 control chromosomes (gnomAD). c.307T>G has been reported in the literature in multiple individuals affected with late onset and infantile forms of Pompe Disease (e.g. Hermans_2004, Remiche_2014). These data indicate that the variant is very likely to be associated with disease. Experimental evidence from an in vitro study reports greater than 98% loss of enzymatic activity (Hermans_2004) for this variant. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Institute of Human Genetics, University of Leipzig Medical Center RCV000811478 SCV001950047 pathogenic Glycogen storage disease, type II 2021-07-08 criteria provided, single submitter clinical testing This variant was identified in trans as compound heterozygous with NM_000152.5:c.-32-13T>G.
Broad Institute Rare Disease Group, Broad Institute RCV000811478 SCV001423069 likely pathogenic Glycogen storage disease, type II 2020-01-22 no assertion criteria provided curation The heterozygous p.Cys103Gly variant in GAA has been reported in 13 individuals (including 8 Germans, 1 Australian, 1 Greek and 1 Italian individuals) with Glycogen Storage Disease II, segregated with disease in 2 affected siblings from 1 family (PMID: 14695532, 22676651, 16838077, 23160972, 18607768, 18429042, 17643989, 24158270, 29565424, 18285536, 28196920), and has also been reported pathogenic by EGL Genetic Diagnostics, Invitae, and GeneDx in ClinVar (Variation ID: 92483). This variant has been identified in 0.006% (1/15414) of European (non-Finnish) chromosome by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs398123174). 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 with COS cells transfected with this variant provide some evidence that the p.Cys103Gly variant may impact GAA protein processing and activity (PMID: 14695532). 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 pathogenic variant and in individuals with Glycogen Storage Disease II increases the likelihood that the p.Cys103Gly variant is pathogenic (PMID: 16838077, 24158270, 20033296, 28196920, 22676651, 18285536). The phenotype of individuals heterozygous for this variant is highly specific for Glycogen Storage Disease II based on reduced GAA activity in relevant tissues, consistent with disease (PMID: 16838077, 24158270, 20033296, 28196920, 22676651, 18285536). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PM3_Supporting, PS3, PM2, PP3, PP4 (Richards 2015).
Natera, Inc. RCV000811478 SCV001453581 pathogenic Glycogen storage disease, type II 2020-09-16 no assertion criteria provided clinical testing

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