Submissions for variant NM_000152.5(GAA):c.1798C>T (p.Arg600Cys)

gnomAD frequency: 0.00002  dbSNP: rs764670084

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel	RCV000794042	SCV002032136	pathogenic	Glycogen storage disease, type II	2021-09-30	reviewed by expert panel	curation	The NM_000152.5:c.1798C>T variant in GAA is a missense variant predicted to cause substitution of arginine by cysteine at amino acid 600 (p.Arg600Cys). At least 15 patients with Pompe disease have been reported with this variant. Of these patients, at least 8 have documented laboratory values showing GAA deficiency, some of whom also have documentation of symptoms consistent with infantile onset Pompe disease, and/or on enzyme replacement therapy, meeting the ClinGen LSD VCEP’s specifications for PP4_Moderate (PMID 14695532, 18458862, 19609281, 21984055, 24384324, 26497565, 29124014) (PP4_Moderate). Additional patients were reported to be on enzyme replacement therapy, without GAA activity values provided, meeting PP4 (PMID 20202878), and others were reported to have Pompe disease but did not have sufficient data for PP4 to be applied (PMID 11053688, 14643388, 26253708, 27417441, 29124014). The patients with Pompe disease and this variant include three patients who are compound heterozygous for the variant and a pathogenic variant in GAA, either c.525delT (PMID 14695532; phase unknown), or c.546G>T (PMID 20202878, 21984055; phase unknown in both cases), and one homozygote (PMID 11053688)(PM3_Strong). The variant was also reported to be in cis with c.199G>A (p.Asp67Asn) and in trans with c.546G>T in one patient; this data was not counted for PM3 due to the presence of the in cis variant, which is rare and has not yet been assessed by the LSD VCEP (PMID 19609281). In addition, the variant was found in compound heterozygosity with the following variants; the allelic data for the following patients will be used in the assessment of the second variant and is not included here to avoid circular logic - c.871C>T (p.Leu291Phe)(PMID 26253708, 27417441), c.872T>C (p.Leu291Pro)(PMID 18458862), c.1211A>G (p.Asp404Gly)(PMID 24384324), c.1309C>T (p.Arg437Cys)(PMID 29124014), c.1316T>A (p.Met439Lys)(PMID 20202878), c.1857C>G (p.Ser619Arg)(PMID 29124014), c.1979G>A (p.Arg660His)(PMID 14643388), c.2105G>T (p.Arg702Leu)(PMID 26497565), c.2481+1G>A (PMID 29124014). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00003 in the South Asian population, which is lower than the ClinGen LSD VCEP’s threshold for PM2_Supporting (<0.001), meeting this criterion (PM2_Supporting). This variant alters an amino acid, Arg600, that has been deduced to be important in the active site architecture of GAA, based on the crystal structure of native and recombinant GAA (PMID: 29061980; DOI 10.1101/212837)(PM1). Indeed, when expressed in either COS cells or GAA-deficient SV40 immortalized fibroblasts, the variant had <1% wild type GAA activity, and Western blot showed abnormal synthesis and processing of the enzyme (PMID 11053688, 14695532) (PS3_Moderate). The computational predictor REVEL gives a score of 0.915 which is above the threshold of 0.7, evidence that correlates with impact to GAA function (PP3). Three additional missense changes in the same codon have been reported in patients with Pompe disease; c.1799G>A (p.Arg600His) is pathogenic based on assessment by the ClinGen LSD VCEP (PM5); c.1799G>C (p.Arg600Pro) and c.1799G>T (p.Arg600Leu) have also been reported. There is a ClinVar entry for this variant (Variant ID 640911; 2 star review status) with three submitters classifying the variant as pathogenic. In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria met, as specified by the ClinGen LSD VCEP (Specifications Version 2.0): PM1, PM5, PP3, PS3_Moderate, PM3_Strong, PM2_Supporting, PP4_Moderate.
Invitae	RCV000794042	SCV000933425	pathogenic	Glycogen storage disease, type II	2023-11-24	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 600 of the GAA protein (p.Arg600Cys). This variant is present in population databases (rs764670084, gnomAD 0.003%). This missense change has been observed in individual(s) with Pompe disease (PMID: 11053688, 20202878, 25213570, 27344650, 29044175, 29124014). ClinVar contains an entry for this variant (Variation ID: 640911). 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: 11053688). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000794042	SCV001363614	pathogenic	Glycogen storage disease, type II	2021-07-05	criteria provided, single submitter	clinical testing	Variant summary: GAA c.1798C>T (p.Arg600Cys) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 248436 control chromosomes. c.1798C>T has been reported in the literature in multiple individuals affected with Glycogen Storage Disease, Type 2 (Pompe Disease) (e.g. Tsujino_2000, Hermans_2004). These data indicate that the variant is very likely to be associated with disease. Several publications report experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity (e.g. Tsujino_200, Hermans_2004). Two other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Both laboratories cited 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	RCV000794042	SCV001422995	pathogenic	Glycogen storage disease, type II	2020-01-22	criteria provided, single submitter	curation	The p.Arg600Cys variant in GAA has been reported in at least 14 individuals with glycogen storage disease II (PMID: 24384324, 19609281, 21982629, 20202878, 18458862, 14695532, 11053688) and has been identified in 0.003% (1/30610) of South Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs764670084). 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 using COS cells and fibroblast cells transfected with the variant provide some evidence that the p.Arg600Cys variant may impact protein function (PMID: 11053688, 14695532). However, these types of assays may not accurately represent biological function. The phenotype of individuals heterozygous for this variant is highly specific for glycogen storage disease II based on GAA enzyme activity in fibroblasts being <10% of wild type, consistent with disease (PMID: 24384324, 19609281, 21982629, 18458862, 14695532, 14643388). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. Additionally, the presence of this variant in combination with reported pathogenic and likely pathogenic variants and in 8 individuals with glycogen storage disease II increases the likelihood that the p.Arg600Cys variant is pathogenic (VariationID: 371305, 4033, 189172; PMID: 24384324, 19609281, 21982629, 20202878, 18458862, 14695532, 14643388). One additional pathogenic variant, resulting in a different amino acid change at the same position, p.Arg600His, has been reported in association with disease in the literature and ClinVar, supporting that a change at this position may not be tolerated (Variation ID: 370130; PMID: 22676651, 21920843, 18757064, 27649523, 24715333, 18995995, 10338092). In summary, this variant meets criteria to be classified as pathogenic for glycogen storage disease II in an autosomal recessive manner based on the presence of the variant in combination with other pathogenic variants in affected individuals, in vitro studies demonstrating an impact on protein function, and the low frequency of the variant in the general population. ACMG/AMP Criteria applied: PM3_strong, PS3, PM5, PM2, PP3, PP4 (Richards 2015).
Revvity Omics, Revvity	RCV001784410	SCV002023808	pathogenic	not provided	2021-09-20	criteria provided, single submitter	clinical testing
DASA	RCV000794042	SCV002061280	pathogenic	Glycogen storage disease, type II	2022-01-05	criteria provided, single submitter	clinical testing	The c.1798C>T;p.(Arg600Cys) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 640911; PMID: 29124014; 11053688; 20202878; 25213570; 27344650; 29044175) - PS4. Well-established in vitro or in vivo functional studies support a damaging effect on the gene or gene product (PMID: 11053688, 14695532) - PS3_moderate. The variant is present at low allele frequencies population databases (rs764670084– gnomAD 0.0001971%; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2_supporting. Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3. In summary, the currently available evidence indicates that the variant is pathogenic.
GeneDx	RCV001784410	SCV003806151	pathogenic	not provided	2022-08-16	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies demonstrate a damaging effect with significantly reduced enzyme activity compared to wildtype (Tsujino et al., 2000; de Faria et al., 2021); This variant is associated with the following publications: (PMID: 34530085, 31254424, 25213570, 20202878, 27344650, 14695532, 24169249, 19343043, 22253258, 25973016, 14643388, 18458862, 24384324, 26497565, 29122469, 11053688, 29124014, 33560568, 29044175, 17805474, 21982629, 19609281)
Baylor Genetics	RCV000794042	SCV004197890	pathogenic	Glycogen storage disease, type II	2022-10-19	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000794042	SCV002092060	pathogenic	Glycogen storage disease, type II	2020-09-15	no assertion criteria provided	clinical testing