Submissions for variant NM_000152.5(GAA):c.2501_2502del (p.Thr834fs)

dbSNP: rs886043343

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel	RCV000285320	SCV001371719	pathogenic	Glycogen storage disease, type II	2020-05-05	reviewed by expert panel	curation	This variant, c.2501_2502delCA (p.Thr834Argfs) is predicted to result in a frameshift causing a premature termination codon, nonsense medicated decay, and lack of GAA gene product, meeting PVS1. The variant has a highest population minor allele frequency of 0.00005794 in the Latino population, meeting PM2. This variant was found in compound heterozygosity with a known pathogenic variant, c.-32-13T>G, in three patients, who all meet the ClinGen LSD VCEP's PP4 criterion (PMID 22958975). The phase not confirmed in any of these patients. Additional patients with this variant have been reported but were not included because the residual GAA activity was not provided, and therefore PP4 cannot be assessed (PMIDs 19588081, 29122469), or the in trans data had been counted towards another variant and therefore were not included here to avoid circular logic (c.1933G>A (p.Asp645Asn), (PMID 23601496). The data meet PP4 and PM3_Supporting. There is a ClinVar entry for this variant (Variant ID: 286229; 2 star review status) with three 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: PVS1, PM2, PM3_Supporting, PP4.
Eurofins Ntd Llc (ga)	RCV000725814	SCV000339572	pathogenic	not provided	2016-02-23	criteria provided, single submitter	clinical testing
Tehran Medical Genetics Laboratory	RCV000285320	SCV000692564	likely pathogenic	Glycogen storage disease, type II		criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000285320	SCV000917399	pathogenic	Glycogen storage disease, type II	2018-11-30	criteria provided, single submitter	clinical testing	Variant summary: GAA c.2501_2502delCA (p.Thr834ArgfsX49) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (eg. c.2544delC, p.Lys849fsX38 and c.2560C>T, p.Arg854X). The variant allele was found at a frequency of 8.1e-06 in 245500 control chromosomes (gnomAD). The variant, c.2501_2502delCA, has been reported in the literature in individuals affected with Glycogen Storage Disease, Type 2 (Pompe Disease)(Kroos_2008, Palermo_2012, Musumeci_2012). These data indicate that the variant is likely to be associated with disease. 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000285320	SCV001379737	pathogenic	Glycogen storage disease, type II	2023-06-04	criteria provided, single submitter	clinical testing	This premature translational stop signal has been observed in individuals with Pompe disease (PMID: 19588081, 22958975, 29122469, 30564623). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 286229). This variant is present in population databases (no rsID available, gnomAD 0.006%). This sequence change creates a premature translational stop signal (p.Thr834Argfs*49) in the GAA gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in GAA are known to be pathogenic (PMID: 18425781, 22252923).
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000285320	SCV001423058	pathogenic	Glycogen storage disease, type II	2020-01-22	criteria provided, single submitter	curation	The p.Thr834ArgfsTer49 variant in GAA has been reported in 8 individuals with Glycogen Storage Disease II (PMID: 22958975, 23601496, 29122469, 19588081), and has also been reported pathogenic by EGL and likely pathogenic by Tehran Medical Genetics Laboratory and Integrated Genetics in ClinVar (Variation ID: 286229). This variant has been identified in 0.0058% (2/34516) of Latino chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs886043343). 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 is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at position 834 and leads to a premature termination codon 49 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the GAA gene is an established disease mechanism in autosomal recessive Glycogen Storage Disease II. The presence of this variant in combination with a reported pathogenic variant and in individuals with Glycogen Storage Disease II increases the likelihood that the p.Thr834ArgfsTer49 variant is pathogenic (PMID: 19588081). The phenotype of individuals heterozygous for this variant is highly specific for Glycogen Storage Disease II based on reduced GAA activity in a dried blood spot or muscle tissue, consistent with disease (PMID: 22958975, 23601496). In summary, this variant meets criteria to be classified as pathogenic for Glycogen Storage Disease II in an autosomal recessive manner based on the predicted impact of the variant and multiple occurrences with pathogenic GAA variants in individuals with Glycogen Storage Disease II. ACMG/AMP Criteria applied: PVS1, PM2, PM3_Supporting, PP4 (Richards 2015).
Revvity Omics, Revvity	RCV000725814	SCV002023880	pathogenic	not provided	2021-02-16	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000285320	SCV002810768	pathogenic	Glycogen storage disease, type II	2021-12-30	criteria provided, single submitter	clinical testing
GeneDx	RCV000725814	SCV005325592	pathogenic	not provided	2023-11-17	criteria provided, single submitter	clinical testing	Observed with a second GAA variant in unrelated patients with GSDII in published literature, but it is not known whether the variants occurred on the same (in cis) or on different (in trans) chromosomes in all cases (PMID: 23601496, 31086307, 30564623); Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at a significant frequency in large population cohorts (gnomAD); Reported in ClinVar but additional evidence is not available (ClinVar Variant ID# 286229; ClinVar); This variant is associated with the following publications: (PMID: 31254424, 19588081, 31589614, 18425781, 23601496, 31086307, 30564623)
Counsyl	RCV000285320	SCV001132394	pathogenic	Glycogen storage disease, type II	2016-11-17	no assertion criteria provided	clinical testing
Natera, Inc.	RCV000285320	SCV001463862	pathogenic	Glycogen storage disease, type II	2020-09-16	no assertion criteria provided	clinical testing