ClinVar Miner

Submissions for variant NM_000152.5(GAA):c.692+1G>C

dbSNP: rs773281453
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard RCV001249008 SCV001422854 pathogenic Glycogen storage disease, type II 2020-01-22 criteria provided, single submitter curation The c.692+1G>C variant has been reported in at least two individuals with glycogen storage disease (PMID: 24395639, 19046416, 28182897, 16917947), and has been identified in 0.001% (1/111256) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs773281453). 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 occurs in the invariant region (+/- 1/2) of the splice consensus sequence and is predicted to cause altered splicing leading to an absent protein. Loss of function of the GAA gene is an established disease mechanism in autosomal recessive glycogen storage disease. The phenotype of individuals heterozygous for this variant is highly specific for glycogen storage disease based on GAA enzyme activity being <10% of wild type in fibroblasts, consistent with disease (PMID: 28182897, 16917947, 24395639). This variant has been seen in combination with reported pathogenic variant c.-32-13T>G and p.Gly549Arg (VariationID: 4027, PMID: 16917947, 16917947, 28182897, 19046416, 24395639) in individuals with glycogen storage disease. In summary, this variant meets criteria to be classified as pathogenic for glycogen storage disease in an autosomal recessive manner based on the prediction that the variant causes loss of function, the detection of the variant in combination with other pathogenic variants in affected individuals, and the low frequency of the variant in the general population. ACMG/AMP Criteria applied: PVS1, PM2, PP4 (Richards 2015).
Invitae RCV001249008 SCV002136351 pathogenic Glycogen storage disease, type II 2022-04-20 criteria provided, single submitter clinical testing 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. ClinVar contains an entry for this variant (Variation ID: 972793). This sequence change affects a donor splice site in intron 3 of the GAA gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in GAA are known to be pathogenic (PMID: 18425781, 22252923). This variant is present in population databases (rs773281453, gnomAD 0.0009%). Disruption of this splice site has been observed in individuals with Pompe disease (PMID: 16917947).

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