Submissions for variant NM_000152.5(GAA):c.1100G>A (p.Trp367Ter)

dbSNP: rs1478500490

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV001248955	SCV001422741	pathogenic	Glycogen storage disease, type II	2020-01-22	criteria provided, single submitter	curation	The p.Trp367Ter variant in GAA has been reported in one Caucasian individual with glycogen storage disease (PMID: 17723315, 18425781), and been identified in 0.001% (1/112382) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs1478500490). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier disease. This nonsense variant leads to a premature termination codon at position 367, which is 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 presence of this variant in combination with reported pathogenic variant c.-32-13T>G (VariationID: 4027; PMID: 17723315) and in an individual with glycogen storage disease increases the likelihood that the p.Trp367Ter variant is pathogenic. The phenotype of an individual compound heterozygous for this variant is highly specific for glycogen storage disease based on their GAA activity being less than 10% of WT, consistent with disease (PMID: 17723315). 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 GAA, and its presence in an affected individual with another pathogenic variant. ACMG/AMP Criteria applied: PVS1, PM2, PM3_supporting, PP4 (Richards 2015).
Labcorp Genetics (formerly Invitae), Labcorp	RCV001248955	SCV002123947	pathogenic	Glycogen storage disease, type II	2022-05-18	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Trp367*) 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 0.0009%). This premature translational stop signal has been observed in individual(s) with clinical features of Pompe disease (PMID: 17723315). ClinVar contains an entry for this variant (Variation ID: 972773). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. For these reasons, this variant has been classified as Pathogenic.