ClinVar Miner

Submissions for variant NM_000152.5(GAA):c.2242dup (p.Glu748fs) (rs777275355)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel, ClinGen RCV000411023 SCV001371704 pathogenic Glycogen storage disease, type II 2020-05-04 reviewed by expert panel curation This variant, c.2242dup (p.Glu748Glyfs), is a frameshift variant predicted to cause a premature termination codon, nonsense mediated decay, and lack of gene product, meeting PVS1. The highest population minor allele frequency in gnomAD is 0.00001767 in the European, non-Finnish, population, meeting PM2. This variant has been reported in at least 2 individuals with Pompe disease and deficient GAA activity meeting the ClinGen LSD VCEP's PP4 specifications (PMIDs 9535769, 21484825). Both of these individuals are compound heterozygous for the variant and a unique variant, phase unknown; either c.1933G>A (p.Asp645Asn) (PMID 9535769) or c.1195-8G>A (PMID 21484825). In both cases, the in trans data from these patients will be used in the assessment of the second variant and was not included here in order to avoid a circular argument. There is a ClinVar entry for this variant (Variation ID 370651; 2 star review status) with three submitters classifying the variant and pathogenic, and one as likely pathogenic. 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 LSD VCEP: PVS1, PM2, PP4.
GeneDx RCV000524025 SCV000617645 pathogenic not provided 2018-09-12 criteria provided, single submitter clinical testing The c.2242dupG pathogenic variant in the GAA gene has been previously reported in multiple individuals with Pompe Disease (Beesley et al., 1998; Montalvo et al., 2006; Bali et al., 2011). One individual harboring the c.2242dupG variant, as well as an additional GAA variant, was found to have <1% of normal GAA activity (Bali et al., 2011). The c.2242dupG variant causes a frameshift starting with codon Glutamic Acid 748, changes this amino acid to a Glycine residue, and creates a premature Stop codon at position 48 of the new reading frame, denoted p.Glu748GlyfsX48. This variant is predicted to cause loss of normal protein function through protein truncation or nonsense-mediated mRNA decay. The c.2242dupG variant is not observed in large population cohorts (Lek et al., 2016). In summary, we interpret c.2242dupG to be a pathogenic variant.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000524025 SCV000706065 pathogenic not provided 2017-01-31 criteria provided, single submitter clinical testing
Invitae RCV000411023 SCV000959782 pathogenic Glycogen storage disease, type II 2019-09-21 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Glu748Glyfs*48) in the GAA gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs777275355, ExAC 0.003%). This variant has been observed in combination with another GAA variant in several individuals affected with glycogen storage disease type II (PMID: 9535769, 16917947, 21484825, 29122469). This variant is also known as insGnt2243 and insG2242 in the literature. ClinVar contains an entry for this variant (Variation ID: 370651). Loss-of-function variants in GAA are known to be pathogenic (PMID: 18425781, 22252923). For these reasons, this variant has been classified as Pathogenic.
Counsyl RCV000411023 SCV000486019 likely pathogenic Glycogen storage disease, type II 2016-03-15 no assertion criteria provided clinical testing
Broad Institute Rare Disease Group,Broad Institute RCV000411023 SCV001423057 pathogenic Glycogen storage disease, type II 2020-01-22 no assertion criteria provided curation The p.Glu748GlyfsTer48 variant in GAA has been reported in at least 5 individuals (including 2 from the UK, and 1 Italian individuals) with Glycogen Storage Disease II (PMID: 16917947, 9535769, 10206684, 21484825), and has also been reported likely pathogenic by Counsyl and pathogenic by GeneDx and EGL in ClinVar (Variation ID: 370651). This variant has been identified in 0.0018% (2/113202) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD,; dbSNP rs1057516659). 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 748 and leads to a premature termination codon 48 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the GAA gene is an established disease mechanism in autosomal recessive Glycogen Storage Disease II. The presence of this variant in combination with at least 2 pathogenic variants curated by our study and in individuals with Glycogen Storage Disease II increases the likelihood that the p.Glu748GlyfsTer48 variant is pathogenic (PMID: 9535769, 29122469). The phenotype of two individuals heterozygous for this variant is highly specific for Glycogen Storage Disease II with abnormally low GAA activity detected in fibroblasts (PMID: 9535769, 21484825). 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 multiple occurrences with pathogenic GAA variants in individuals with Glycogen Storage Disease II. ACMG/AMP Criteria applied: PVS1, PM3, PM2, PP4 (Richards 2015).

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