ClinVar Miner

Submissions for variant NM_000152.5(GAA):c.2407C>T (p.Gln803Ter)

gnomAD frequency: 0.00002  dbSNP: rs1344266804
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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 RCV000667612 SCV001371717 pathogenic Glycogen storage disease, type II 2023-07-03 reviewed by expert panel curation The NM_000152.5:c.2407C>T (p.Gln803Ter) variant in GAA is a nonsense variant predicted to cause a premature stop codon in biologically-relevant-exon 17 (out of 20 exons), leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). One patient with late onset Pompe disease with this variant and treated by enzyme replacement therapy has been reported (PP4). This individual is compound heterozygous for the variant and "IVS 0-45T>G" (assumed to be c.-32-13T>G), a pathogenic variant in GAA, phase unknown (PMID: 26572913) (PM3_Supporting). Two additional patients have been reported to be compound heterozygous for p.Gln803Ter but the cDNA change provided is incorrect and thus this data was not included (PMID: 21940687). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00001 (1/111412 alleles) in the European-Non-Finnish population, which is lower than the ClinGen Lysosomal Diseases VCEP threshold (<0.001) for PM2_Supporting, meeting this criterion. There is a ClinVar entry for this variant (Variation ID: 552368). 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 Lysosomal Diseases VCEP (Specifications Version 2.0): PVS1, PP4, PM2_Supporting, PM3_Supporting. (Classification approved by the ClinGen Lysosomal Diseases VCEP, July 3, 2023)
Counsyl RCV000667612 SCV000792090 pathogenic Glycogen storage disease, type II 2017-06-20 criteria provided, single submitter clinical testing
Invitae RCV000667612 SCV001389884 pathogenic Glycogen storage disease, type II 2023-10-23 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Gln803*) 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). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individual(s) with Pompe disease (PMID: 26572913). ClinVar contains an entry for this variant (Variation ID: 552368). For these reasons, this variant has been classified as Pathogenic.
Revvity Omics, Revvity RCV001784249 SCV002023852 pathogenic not provided 2020-10-19 criteria provided, single submitter clinical testing
Baylor Genetics RCV000667612 SCV004195482 pathogenic Glycogen storage disease, type II 2023-09-18 criteria provided, single submitter clinical testing

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