ClinVar Miner

Submissions for variant NM_000152.5(GAA):c.1856G>A (p.Ser619Asn) (rs753269119)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000409055 SCV000485388 likely pathogenic Glycogen storage disease, type II 2015-11-30 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000409055 SCV001361531 pathogenic Glycogen storage disease, type II 2019-01-10 criteria provided, single submitter clinical testing Variant summary: GAA c.1856G>A (p.Ser619Asn) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.7e-05 in 237486 control chromosomes (gnomAD). The variant, c.1856G>A, has been reported in the literature in individuals affected with Glycogen Storage Disease, Type 2 (Pompe Disease)(Kroos_2006, Remiche_2014, Gallardo_2011, Parenti_2014, Arslan_2016). One patient, Arslan_2016, was found to be homozygous for two deleterious variants, the variant of interest and c.32-13T>G, to which the authors indicate the phenotype was more progressive. The patient was born to consanguineous Turkish parents. These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of residual acid -glucosidase activity (Kroos_2006). A ClinVar submission from a clinical diagnostic laboratory (evaluation after 2014) cites the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae RCV000409055 SCV001409389 pathogenic Glycogen storage disease, type II 2019-08-26 criteria provided, single submitter clinical testing This sequence change replaces serine with asparagine at codon 619 of the GAA protein (p.Ser619Asn). The serine residue is highly conserved and there is a small physicochemical difference between serine and asparagine. This variant is present in population databases (rs753269119, ExAC 0.03%). This variant has been observed in several individuals affected with Pompe disease (PMID: 16838077, 25998610, 24158270, 26946079, 22990675). ClinVar contains an entry for this variant (Variation ID: 370146). This variant has been reported to affect GAA protein function (PMID: 19862843). This variant disrupts the p.Ser619 amino acid residue in GAA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 21471980, 25213570, 27363342, 29124014, 14643388). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Broad Institute Rare Disease Group,Broad Institute RCV000409055 SCV001422906 pathogenic Glycogen storage disease, type II 2020-01-22 no assertion criteria provided curation The p.Ser619Asn variant in GAA has been reported in 8 individuals with Glycogen Storage Disease II (PMID: 22194990, 26946079, 22980766, 16838077, 24158270, 25052852, 23668440, 25998610). This variant has also been reported likely pathogenic by Counsyl in ClinVar (Variation ID: 370146) and has been identified in 0.013% (4/29974) of South Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs753269119). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. In vitro functional studies provide some evidence that the p.Ser619Asn variant may impact proteolytic activation of GAA and GAA activity (PMID: 16838077, 19862843). However, these types of assays may not accurately represent biological function. 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 pathogenic additional variant at the the same position, p.Ser619Arg, has been reported in association with disease in ClinVar, supporting that a change at this position may not be tolerated (Variation ID: 550825). The presence of this variant in combination with a pathogenic variant and in an individual with Glycogen Storage Disease II increases the likelihood that the p.Ser619Asn variant is pathogenic (PMID: 16838077). Of note, this variant has also been observed in cis with the known pathogenic variant c.-32-13T>G with both variants in the homozygous state in an individual with Glycogen Storage Disorder II (PMID: 26946079). The phenotype of individuals homozygous and heterozygous for this variant is highly specific for Glycogen Storage Disease II based on reduced GAA activity in relevant tissue, consistent with disease (PMID: 24158270, 26946079, 16838077). In summary, this variant meets criteria to be classified as pathogenic for Glycogen Storage Disease II in an autosomal recessive manner based on in vitro functional studies, another pathogenic variant at the same position, and low frequency in the general population. ACMG/AMP Criteria applied: PS3, PM2, PM5, PP3, PM3_Supporting, PP4 (Richards 2015).

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