Submissions for variant NM_000152.5(GAA):c.1496G>A (p.Trp499Ter)

dbSNP: rs766680292

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel	RCV000673032	SCV001443321	pathogenic	Glycogen storage disease, type II	2020-10-05	reviewed by expert panel	curation	This variant, c.1496G>A (p.Trp499Ter) is a nonsense variant which is predicted to cause nonsense mediated decay resulting in lack of gene product. This is supported by the absence of cross reactive immunological material in cultured skin fibroblasts from a patient with this variant (PMIDs 19775921, 22252923, and 25741864). Therefore, PVS1 can be applied. This patient, who has infantile onset Pompe disease, meets the ClinGen LSD VCEP's specifications for PP4, and is homozygous for the variant, meeting PM3_Supporting. Additional patients have been reported, including 2 homozygous Tunisian patients (PMID 32125626), but the residual GAA activity was not provided, and this data was not included. The highest population minor allele frequency in gnomAD v2.1.1 is 0.00003 in the Latino population, which meets PM2. There is a ClinVar entry for this variant (Variation ID 556959, 1 star review status), with one submitter 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. ACMG/AMP criteria met, based on the specifications of the ClinGen LSD VCEP: PVS1, PM2, PM3_Supporting, PP4.
Counsyl	RCV000673032	SCV000798197	likely pathogenic	Glycogen storage disease, type II	2018-03-01	criteria provided, single submitter	clinical testing
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000673032	SCV001422697	pathogenic	Glycogen storage disease, type II	2020-01-23	criteria provided, single submitter	curation	The p.Trp499Ter variant in GAA has been reported in at least 3 individuals with glycogen storage disease (PMID: 19775921, 18425781, 22252923) and has been identified in 0.003% (1/34586) Latino chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs766680292). 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 has also been reported in ClinVar as likely pathogenic by Counsyl (Variation ID: 556959). This nonsense variant leads to a premature termination codon at position 499, 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 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: 19775921). Additionally, the homozygous occurrence of this variant and in an individual with glycogen storage disease (PMID: 19775921) slightly increases the likelihood that the p.Trp499Ter variant is pathogenic. In summary, this variant meets criteria to be classified as pathogenic for GAA in an autosomal recessive manner based on the prediction that it causes loss of function of the GAA gene, its low frequency in the general population, and the homozygous occurrence of the variant in an affected individual. ACMG/AMP Criteria applied: PVS1, PM2, PP4, PM3_supporting (Richards 2015).
Labcorp Genetics (formerly Invitae), Labcorp	RCV000673032	SCV002184849	pathogenic	Glycogen storage disease, type II	2024-12-30	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Trp499*) 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 (rs766680292, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with Pompe disease (PMID: 18425781). ClinVar contains an entry for this variant (Variation ID: 556959). For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics	RCV000673032	SCV005058767	pathogenic	Glycogen storage disease, type II	2023-11-22	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000673032	SCV005653207	pathogenic	Glycogen storage disease, type II	2024-04-18	criteria provided, single submitter	clinical testing