Submissions for variant NM_000152.5(GAA):c.1076-22T>G

gnomAD frequency: 0.00002  dbSNP: rs762260678

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000409600	SCV000485540	likely pathogenic	Glycogen storage disease, type II	2016-01-05	criteria provided, single submitter	clinical testing
Invitae	RCV000409600	SCV001205933	pathogenic	Glycogen storage disease, type II	2023-07-07	criteria provided, single submitter	clinical testing	Studies have shown that this variant results in skipping of exon 6, but is expected to preserve the integrity of the reading-frame (PMID: 9259196). ClinVar contains an entry for this variant (Variation ID: 370278). This variant is also known as IVS6-22T>G. This variant has been observed in individual(s) with glycogen storage disease type II (GSD II) (PMID: 9259196, 10737124, 22613277). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs762260678, gnomAD 0.003%). This sequence change falls in intron 6 of the GAA gene. It does not directly change the encoded amino acid sequence of the GAA protein. RNA analysis indicates that this variant induces altered splicing and likely results in a shortened protein product. For these reasons, this variant has been classified as Pathogenic.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000409600	SCV001422619	pathogenic	Glycogen storage disease, type II	2020-01-22	criteria provided, single submitter	curation	The c.1076-22T>G variant in GAA has been reported in 8 individuals (including 3 Germans, 2 Dutch, and 1 African American/Caucasian individuals) with Glycogen Storage Disorder II (PMID: 10737124, 9259196, 25455803, 22613277, 21484825, 22676651, 23013746), and has also been reported likely pathogenic by Counsyl in ClinVar (Variation ID: 370278). This variant has been identified in 0.003% (3/112848) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs762260678). 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 with RNA extracted from individuals homozygous for this variant provide some evidence that the c.1076-22T>G variant may cause abnormal splicing (PMID: 10737124). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses suggest that this variant may impact splicing, though this information is not predictive enough to determine pathogenicity. The presence of this variant in the homozygous state and in combination with pathogenic variants, and in individuals with Glycogen Storage Disorder II increases the likelihood that the c.1076-22T>G variant is pathogenic (PMID: 10737124, 22676651, 22613277, 9259196, 21484825). The phenotype of homozygous and heterozygous individuals with this variant is highly specific for Glycogen Storage Disease II based on reduced GAA activity detected in relevant tissues (PMID: 10737124, 22676651, 22613277, 9259196, 21484825). In summary, this variant meets criteria to be classified as pathogenic for Glycogen Storage Disorder II in an autosomal recessive manner based on in vitro functional studies and multiple occurrences with pathogenic variants. ACMG/AMP Criteria applied: PM3_Strong, PS3, PM2, PP3, PP4 (Richards 2015).
GeneDx	RCV001570177	SCV001794408	pathogenic	not provided	2019-10-29	criteria provided, single submitter	clinical testing	Predicted to create a strong cryptic splice acceptor site upstream of the natural splice acceptor site of intron 6 and analysis of patient cDNA demonstrates an in-frame insertion of 21 nucleotides and skipping of exon 6 causing insertion of 7 incorrect amino acids and loss of 40 amino acids encoded by exon 6 (Adams et al., 1997; Vorgerd et al., 1998); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 31342611, 29181627, 9259196, 22613277, 10737124, 17643989, 21179066, 21484825, 27408821, 22676651, 25455803, 23013746, 9529346)
Revvity Omics, Revvity	RCV001570177	SCV002023834	pathogenic	not provided	2021-09-20	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000409600	SCV004197914	pathogenic	Glycogen storage disease, type II	2022-03-30	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000409600	SCV001455603	pathogenic	Glycogen storage disease, type II	2020-09-16	no assertion criteria provided	clinical testing