Submissions for variant NM_000152.5(GAA):c.1062C>A (p.Tyr354Ter)

dbSNP: rs1064796703

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel	RCV001265224	SCV001443302	pathogenic	Glycogen storage disease, type II	2023-04-19	reviewed by expert panel	curation	The NM_000152.5:c.1062C>A (p.Tyr354Ter) variant in GAA is a nonsense variant predicted to cause a premature stop codon in biologically-relevant-exon 6/20, leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). One patient with infantile onset Pompe disease, identified by newborn screen and treated with enzyme replacement therapy, has been reported (PMID: 32373469) (PP4). This patient is compound heterozygous for the variant and a variant in GAA that has been classified as pathogenic by the ClinGen LD VCEP, c.1935C>A (p.Asp645Glu) (PMID: 32373469) (PM3_Supporting). There is a ClinVar entry for this variant (Variation ID: 423925). 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 Lysosomal Diseases VCEP (Specifications version 2.0): PVS1, PM3_Supporting, PM2_Supporting. (Classification approved by the ClinGen Lysosomal Diseases VCEP, April 11, 2023).
GeneDx	RCV000479891	SCV000573688	pathogenic	not provided	2017-03-10	criteria provided, single submitter	clinical testing	The Y354X variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The Y354X variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The Y354X variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. Although Y354X has not been previously reported to our knowledge, other downstream nonsense variants in the GAA gene have been reported in the Human Gene Mutation Database in association with GSDII (Stenson et al., 2014). Therefore, we interpret Y354X as a pathogenic variant.
Fulgent Genetics, Fulgent Genetics	RCV001265224	SCV002777053	likely pathogenic	Glycogen storage disease, type II	2021-11-22	criteria provided, single submitter	clinical testing
Invitae	RCV001265224	SCV004486811	pathogenic	Glycogen storage disease, type II	2023-10-24	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Tyr354*) 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 not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with Pompe disease (PMID: 18425781, 31076647). ClinVar contains an entry for this variant (Variation ID: 423925). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.