ClinVar Miner

Submissions for variant NM_000152.5(GAA):c.1802C>G (p.Ser601Trp) (rs374470794)

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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 RCV000597451 SCV000708291 likely pathogenic not provided 2017-05-10 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001199859 SCV001370595 likely pathogenic Glycogen storage disease, type II 2020-05-01 criteria provided, single submitter clinical testing Variant summary: GAA c.1802C>G (p.Ser601Trp) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 248082 control chromosomes (gnomAD). c.1802C>G has been reported in the literature in individuals (in compound heterozygous state) affected with Glycogen Storage Disease, Type 2 (Pompe Disease) (Angelini_2012, Palmer_2007, DeFilippi_2014, Parini_2018). These data indicate that the variant is likely to be associated with disease. Most of the patients from these reports had late onset phenotype of the disease. In in vitro functional studies, the variant was found to have reduced enzymatic activity (Flanagan_2009). One ClinVar submitter (evaluation after 2014) cite the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Broad Institute Rare Disease Group, Broad Institute RCV001199859 SCV001422903 likely pathogenic Glycogen storage disease, type II 2020-01-22 no assertion criteria provided curation The p.Ser601Trp variant in GAA has been reported in one Italian individual with Glycogen Storage Disease II (PMID: 17056254) and has also been reported likely pathogenic by EGL in ClinVar (Variation ID: 501793). This variant was absent from large population studies. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. One additional likely pathogenic variant has been reported at the the same position, p.Ser601Leu, slightly supporting that a change at this position may not be tolerated (Variation ID: 194154; PMID: 30023291, 22676651, 22644586). The presence of this variant in combination with a pathogenic variant curated by our study and in an individual with Glycogen Storage Disease II increases the likelihood that the p.Ser601Trp variant is pathogenic (PMID: 17056254). The phenotype of the individual with this variant is highly specific for Glycogen Storage Disease II based on abnormally low GAA activity detected in lymphocytes (PMID: 17056254). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PM2, PM5_Supporting, PP3, PM3_Supporting, PP4 (Richards 2015).

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