ClinVar Miner

Submissions for variant NM_000152.5(GAA):c.1076-22T>G (rs762260678)

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Total submissions: 5
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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 2020-08-29 criteria provided, single submitter clinical testing 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. This variant is present in population databases (rs762260678, ExAC 0.005%). This variant has been observed to segregate with glycogen storage disease type II (GSD II) in a family and has also been observed in several individuals affected GSD II (PMID: 10737124, 9259196, 22613277). ClinVar contains an entry for this variant (Variation ID: 370278). Experimental studies have shown that this variant disrupts mRNA splicing (PMID: 9259196, 10737124). For these reasons, this variant has been classified as Pathogenic.
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)
Broad Institute Rare Disease Group, Broad Institute RCV000409600 SCV001422619 pathogenic Glycogen storage disease, type II 2020-01-22 no assertion criteria provided 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,; 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).
Natera, Inc. RCV000409600 SCV001455603 pathogenic Glycogen storage disease, type II 2020-09-16 no assertion criteria provided clinical testing

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