Submissions for variant NM_000152.5(GAA):c.1441del (p.Trp481fs)

gnomAD frequency: 0.00001  dbSNP: rs1403500889

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV001248927	SCV001422698	pathogenic	Glycogen storage disease, type II	2020-01-22	criteria provided, single submitter	curation	The p.Trp481GlyfsTer39 variant in GAA has been reported in one African American individual with glycogen storage disease (PMID: 10189220, 25488666), and has been identified in 0.006% (1/16204) of African chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs1403500889). 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 provide some evidence that the p.Trp481GlyfsTer39 variant may result in null protein activity (PMID: 25488666, 2203258, 9614571). However, these types of assays may not accurately represent biological function. This variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at position 481 and leads to a premature termination codon 39 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. The phenotype of an individual homozygous for this variant is highly specific for glycogen storage disease based on GAA enzyme activity in fibroblasts being <1% of wild type, consistent with disease (PMID: 2112341). Additionally, the presence of this variant in combination with reported pathogenic variant p.Trp746Ter (VariationID: 280063) and in an individual with glycogen storage disease has been reported (PMID: 25488666). In summary, this variant meets criteria to be classified as pathogenic for glycogen storage disease in an autosomal recessive manner based on its prediction to cause loss of function of the protein, the rarity of this variant in the general population, and the presence of the variant in a patient severely affected with glycogen storage disease. ACMG/AMP Criteria applied: PVS1, PM2, PP4 (Richards 2015).
Revvity Omics, Revvity	RCV001780191	SCV002023810	pathogenic	not provided	2021-04-14	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001248927	SCV003844464	likely pathogenic	Glycogen storage disease, type II	2023-02-09	criteria provided, single submitter	clinical testing	Variant summary: GAA c.1441delT (p.Trp481GlyfsX39) 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 and in ClinVar. The variant allele was found at a frequency of 4e-06 in 250840 control chromosomes (gnomAD). c.1441delT has been reported in the literature in at-least one individual affected with Glycogen Storage Disease, Type 2 (Pompe Disease) (example: Raben_1999 and Raval_2015). Two submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Baylor Genetics	RCV001248927	SCV004195517	pathogenic	Glycogen storage disease, type II	2023-08-06	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001248927	SCV004296871	pathogenic	Glycogen storage disease, type II	2023-07-07	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Trp481Glyfs*39) 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). This variant is present in population databases (no rsID available, gnomAD 0.007%). For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. ClinVar contains an entry for this variant (Variation ID: 972761). This premature translational stop signal has been observed in individual(s) with infantile glycogen storage disease (PMID: 10189220, 25488666).
GeneDx	RCV001780191	SCV005325566	pathogenic	not provided	2023-08-14	criteria provided, single submitter	clinical testing	Identified in a patient with GSD type II in published literature, however a second mutation in GAA was not identified (Raben et al., 1999); Not observed at significant frequency in large population cohorts (gnomAD); 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; This variant is associated with the following publications: (PMID: 25488666, 33293555, 31254424, 10189220, 2112341)