ClinVar Miner

Submissions for variant NM_000152.5(GAA):c.172C>T (p.Gln58Ter)

gnomAD frequency: 0.00001  dbSNP: rs201185475
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel RCV000169263 SCV001371756 pathogenic Glycogen storage disease, type II 2020-04-20 reviewed by expert panel curation This variant, c.172C>T (p.Gln58Ter), is a nonsense variant, predicted to result in nonsense-mediated decay and lack of gene product, meeting PVS1. The variant is not in gnomAD v2.1.1, meeting PM2. This variant was found in compound heterozygosity with a pathogenic variant in two patients who meet the ClinGen LSD VCEP's PP4 specifications; one with c.525delT, confirmed in trans (PMID 10377006), and the other with c.841C>T (p.Arg281Trp), identified in a clinical diagnostic laboratory. This data meets PM3. Of note, pseudodeficiency variants are absent in the latter patient, allowing PP4_Moderate to be applied. Additional patients have been reported but were not included because the residual GAA activity was not provided and therefore PP4 cannot be assessed (PMID 20817528). There is a ClinVar entry for this variant (Variation ID: 188903, 1 star review status) with one submitter classifying the variant as likely pathogenic. In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease. ACMG/AMP criteria applied, as specified by the ClinGen LSD VCEP: PVS1, PM2, PM3, PP4_Moderate.
Counsyl RCV000169263 SCV000220554 likely pathogenic Glycogen storage disease, type II 2014-07-25 criteria provided, single submitter literature only
Labcorp Genetics (formerly Invitae), Labcorp RCV000169263 SCV001410342 pathogenic Glycogen storage disease, type II 2023-08-30 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 188903). This premature translational stop signal has been observed in individual(s) with glycogen storage disease (PMID: 10377006). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Gln58*) in the GAA gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in GAA are known to be pathogenic (PMID: 18425781, 22252923).
Natera, Inc. RCV000169263 SCV002091890 pathogenic Glycogen storage disease, type II 2020-06-06 no assertion criteria provided clinical testing

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