ClinVar Miner

Submissions for variant NM_000152.5(GAA):c.1128_1129delinsC (p.Trp376fs) (rs786204646)

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Total submissions: 5
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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 RCV000169433 SCV001371728 pathogenic Glycogen storage disease, type II 2020-02-14 reviewed by expert panel curation This variant, c.1128_1129delGGinsC (p.Trp376Cysfs), is a frameshift variant that is predicted to result in a premature termination codon, nonsense mediated decay, and lack of gene product. Therefore, PVS1 can be applied. The variant is absent in gnomAD v2.1.1, meeting PM2. Two individuals have been reported who meet the ClinGen LSD VCEP's specifications for PP4 and who are compound heterozygous for c.1128_1129delGGinsC (p.Trp376Cysfs) and a unique pathogenic variant in GAA; one individual has infantile-onset Pompe disease and is compound heterozygous for the variant and c.2237G>A (p.Trp746Ter), phase unknown (PMID 22237443), the second individual has late onset Pompe disease and is compound heterozygous for the variant and c.-32-13T>G, phase unknown (PMID 26873529). Based on this data, PM3 can be applied. Additional cases have been reported but were not included for PM3 because the residual GAA activity was not reported and therefore PP4 cannot be assessed (PMIDs 29523196, 27408821), full HGVS nomenclature was not provided (PMID 20033296), or the second variant is a variant of unknown significance (PMID 18607768). There is a ClinVar entry for this variant (Variation ID: 189041, 2 star review status) with 3 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, PM3, PM2, PP4.
Counsyl RCV000169433 SCV000220846 likely pathogenic Glycogen storage disease, type II 2014-10-28 criteria provided, single submitter literature only
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000725812 SCV000339553 pathogenic not provided 2017-04-03 criteria provided, single submitter clinical testing
Invitae RCV000169433 SCV000961782 pathogenic Glycogen storage disease, type II 2019-10-14 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Trp376Cysfs*16) in the GAA gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs754134578, ExAC 0.002%). This variant has been observed in several individuals affected with glycogen storage disease (PMID: 18425781, 18607768, 22252923, 22676651). ClinVar contains an entry for this variant (Variation ID: 189041). Loss-of-function variants in GAA are known to be pathogenic (PMID: 2252923, 18425781, 22252923). For these reasons, this variant has been classified as Pathogenic.
Molecular Therapies Laboratory,Murdoch University RCV000169433 SCV001244228 pathogenic Glycogen storage disease, type II 2019-01-07 no assertion criteria provided clinical testing

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