ClinVar Miner

Submissions for variant NM_000152.5(GAA):c.1143del (p.Ala382fs) (rs757458607)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000727139 SCV000706085 pathogenic not provided 2017-02-02 criteria provided, single submitter clinical testing
Counsyl RCV000411575 SCV000485524 likely pathogenic Glycogen storage disease, type II 2015-12-29 no assertion criteria provided clinical testing
Broad Institute Rare Disease Group,Broad Institute RCV000411575 SCV001422881 pathogenic Glycogen storage disease, type II 2020-01-22 no assertion criteria provided curation The p.Ala382LeufsTer10 variant in GAA has been reported in 4 Caucasian individuals (including 2 Germans) with Glycogen Storage Disease II (PMID: 24383498, 22676651), and has also been reported likely pathogenic by Counsyl and pathogenic by EGL in ClinVar (Variation ID: 370263). This variant has been identified in 0.0009% (1/111784) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs1057516359). 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 is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at position 382 and leads to a premature termination codon 10 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. The presence of this variant in combination with a pathogenic variant curated by our study and in 2 individuals with Glycogen Storage Disease II slightly increases the likelihood that the p.Ala382LeufsTer10 variant is pathogenic (PMID: 22676651). The phenotype of individuals compound heterozygous for this variant is highly specific for Glycogen Storage Disease II based on low GAA activity consistent with disease (PMID: 22676651). In summary, this variant meets criteria to be classified as pathogenic for Glycogen Storage Disease II in an autosomal recessive manner based on the predicted impact of the variant and a few occurrences with a pathogenic GAA variant in individuals with Glycogen Storage Disease II. ACMG/AMP Criteria applied: PVS1, PM3_supporting, PM2, PP4 (Richards 2015).

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