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

gnomAD frequency: 0.00003  dbSNP: rs398123174

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel	RCV000811478	SCV002817442	pathogenic	Glycogen storage disease, type II	2022-09-21	reviewed by expert panel	curation	The NM_000152.5: c.307T>G variant in GAA is a missense variant predicted to cause substitution of cysteine by glycine at amino acid 103 (p.Cys103Gly). This variant has been reported in at least 12 patients who have been diagnosed with Pompe disease, including patients with documented GAA deficiency in the affected range in dried blood spot, leukocytes, and fibroblasts and <10% normal GAA activity in muscle (PMIDs: 16838077, 18285536, 21109266, 22676651, 24011652, 24158270, 29803406; Pediatr Pol 2021; 96 (3): 220–222; https://doi.org/10.5114/polp.2021.109310) and three on enzyme replacement therapy (PMID: 18607768, 29565424, 29803406, 23160972) (PP4_Moderate). Of note, in some of these patients, the variant was noted to be in cis with another variant (p.Asp91Asn) which can falsely lower GAA activity in in vitro assays when the substrate is glycogen, but not when the substrate is an artificial substrate, 4-MU. This was taken into account when utilizing GAA activity data. Of the reported patients, at least 11 patients compound heterozygous for the variant, phase unknown, and a known pathogenic variant in GAA including c.-32-13T>G (9 patients, PMID: 16838077, 18285536, 18607768, 21109266, 22676651, 23160972, 24011652, 24158270, 29803406; Pediatr Pol 2021; 96 (3): 220–222; https://doi.org/10.5114/polp.2021.109310), c.525delT (PMID: 14695532) and c.2481+102_c.2646+31del (PMID: 29565424). In addition, one patient is compound heterozygous for the variant and c.1465G>A (p.Asp489Asn) (PMID: 18429042). The allelic data from this patient will be used in the assessment of p.Asp489Asn and is not included here to avoid circular logic. For another patient, the cDNA change for the variants was not provided and therefore the data was not included (PMID: 28196920). The highest population minor allele frequency in gnomAD is 0.00001 (1/126998 alleles) in the European non-Finnish population, which is lower than the ClinGen LSD VCEP threshold (<0.001) for PM2_Supporting, meeting this criterion (PM2_Supporting). When expressed in COS cells, the variant resulted in 1.5% normal activity, and evidence of abnormal GAA processing on Western blot (PMID: 14695532) (PS3_Moderate). The computational predictor REVEL gives a score of 0.985 which is above the threshold of 0.7, evidence that correlates with impact to GAA function (PP3). Two other amino acid substitutions at the same position have been reported in patients with Pompe disease - c.307T>C (p.Cys103Arg) (PMIDs 21984055, 22644586) and c.309C>G (p.Cys103Trp) (PMID 27142047); the classification of p.Cys103Gly will be used to support the classification of these other variants. Therefore, the data is not used here to avoid circular logic. There is a ClinVar entry for this variant (Variation ID: 92483, 2 star review status) with 8 submitters classifying the variant as pathogenic and one as likely pathogenic. In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen LSD VCEP: PM3_Strong, PS3_Moderate, PP4_Moderate, PP3, PM2_Supporting. (Approved by the ClinGen LSD VCEP on Sept. 21, 2022).
Eurofins Ntd Llc (ga)	RCV000078179	SCV000227028	pathogenic	not provided	2012-11-14	criteria provided, single submitter	clinical testing
GeneDx	RCV000078179	SCV000322396	pathogenic	not provided	2023-04-28	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies demonstrate that this variant leads to approximately 98% loss of lysosomal alpha glucosidase activity (Hermans et al., 2004); Located in the Trefoil Type-P Domain (Kroos et al., 2012; Sugawara et al., 2009); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 24158270, 27189384, 27142047, 31254424, 21109266, 18429042, 29181627, 31301153, 31086307, 30105547, 33560568, 22253258, 19343043, 34852371, 14695532, 18607768)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000811478	SCV000951746	pathogenic	Glycogen storage disease, type II	2024-01-04	criteria provided, single submitter	clinical testing	This sequence change replaces cysteine, which is neutral and slightly polar, with glycine, which is neutral and non-polar, at codon 103 of the GAA protein (p.Cys103Gly). This variant is present in population databases (rs398123174, gnomAD 0.0008%). This missense change has been observed in individual(s) with glycogen storage disease type II (PMID: 14695532, 18429042, 18607768, 21109266, 24158270, 29181627). ClinVar contains an entry for this variant (Variation ID: 92483). 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%. Experimental studies have shown that this missense change affects GAA 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.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000811478	SCV001423069	likely pathogenic	Glycogen storage disease, type II	2020-01-22	criteria provided, single submitter	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).
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.
Revvity Omics, Revvity	RCV000078179	SCV002021199	pathogenic	not provided	2023-05-18	criteria provided, single submitter	clinical testing
AiLife Diagnostics, AiLife Diagnostics	RCV000078179	SCV002502991	pathogenic	not provided	2022-02-28	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000811478	SCV002809705	likely pathogenic	Glycogen storage disease, type II	2021-10-23	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000811478	SCV004197796	pathogenic	Glycogen storage disease, type II	2024-03-03	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000078179	SCV004811748	pathogenic	not provided	2024-03-01	criteria provided, single submitter	clinical testing	GAA: PM3:Very Strong, PM2, PM5, PP4, PS3:Supporting
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV004017390	SCV004847980	pathogenic	Glycogen storage disease	2015-12-23	criteria provided, single submitter	clinical testing	The p.Cys103Gly variant in GAA has been reported in 7 individuals with glycogen storage disease II, all of whom were compound heterozygous with a second pathogenic GAA variant (Hermans 2004, Kroos 2007, Joshi 2008, Fidzianska 2011, Remiche 2014). This variant was absent from large population studies. In vitro functional studies provide some evidence that the p.Cys103Gly variant may impact protein function (Hermans 2004). In summary, this variant meets our criteria to be classified as pathogenic for glycogen storage disease II in an autosomal recessive manner based upon absence from controls and multiple occurrences with pathogenic GAA variants in individuals with glycogen storage disease II.
Natera, Inc.	RCV000811478	SCV001453581	pathogenic	Glycogen storage disease, type II	2020-09-16	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004751256	SCV005360439	pathogenic	GAA-related disorder	2024-08-09	no assertion criteria provided	clinical testing	The GAA c.307T>G variant is predicted to result in the amino acid substitution p.Cys103Gly. This variant was reported in the compound heterozygous state in multiple patients with Pompe disease (Hermans et al. 2004. PubMed ID: 14695532; Fidziańska A et al. 2010. PubMed ID: 21109266; Remiche et al. 2013. PubMed ID: 24158270; Löscher et al. 2017. PubMed ID: 29181627). In one patient, GAA residual activity in muscle tissue was ~5% (Remiche et al. 2013. PubMed ID: 24158270). In vitro functional characterization also suggests that this variant is deleterious (Hermans et al. 2004. PubMed ID: 14695532). This variant is classified as pathogenic by the majority of submitters in Clinvar including the ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel (https://www.ncbi.nlm.nih.gov/clinvar/variation/92483/). This variant is reported in 0.00079% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic.