ClinVar Miner

Submissions for variant NM_000152.5(GAA):c.2297A>C (p.Tyr766Ser) (rs144016984)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000486923 SCV000568678 pathogenic not provided 2017-03-28 criteria provided, single submitter clinical testing The Y766S variant has been reported previously in patients with Pompe disease (Yonee et al. 2012; Bali et al. 2015). Patients who are homozygous for Y766S are described as having infantile-onset Pompe disease (Bali et al., 2015). The Y766S variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The Y766S variant is a semi-conservative amino acid substitution. This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. In summary, we interpret Y766S as pathogenic.
Invitae RCV001065031 SCV001229969 pathogenic Glycogen storage disease, type II 2020-03-30 criteria provided, single submitter clinical testing This sequence change replaces tyrosine with serine at codon 766 of the GAA protein (p.Tyr766Ser). The tyrosine residue is highly conserved and there is a large physicochemical difference between tyrosine and serine. This variant is present in population databases (rs144016984, ExAC 0.01%). This variant has been observed in individuals affected with Pompe disease (PMID: 22521436, 28394184, 22538254, external communication). ClinVar contains an entry for this variant (Variation ID: 420102). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant disrupts the p.Tyr766 amino acid residue in GAA. Other variant(s) that disrupt this residue have been observed in individuals with GAA-related conditions (PMID: 29124014, 21605996), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001065031 SCV001339198 pathogenic Glycogen storage disease, type II 2020-03-16 criteria provided, single submitter clinical testing Variant summary: GAA c.2297A>C (p.Tyr766Ser) 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 allele was found at a frequency of 4e-06 in 250124 control chromosomes. c.2297A>C has been reported in the literature in multiple individuals affected with Glycogen Storage Disease, Type 2 (Pompe Disease, Yonee_2012, Bali_2015, Chen_2017). These data indicate that the variant is very likely to be associated with disease. At least one publication showed that variant effect results in <10% of normal activity (Yonee_2012). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Broad Institute Rare Disease Group, Broad Institute RCV001065031 SCV001423071 likely pathogenic Glycogen storage disease, type II 2020-01-22 no assertion criteria provided curation The p.Tyr766Ser variant in GAA has been reported in 6 individuals (including 1 Japanese individual and 1 Chinese individual) with Glycogen Storage Disease II (PMID: 26693141, 21637107, 22521436), and has also been reported pathogenic by GeneDx in ClinVar (Variation ID: 420102). This variant has been identified in 0.005% (1/18378) of East Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs144016984). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. The presence of this variant in the homozygous state and in combination with a pathogenic variant, and in individuals with Glycogen Storage Disease II increases the likelihood that the p.Tyr766Ser variant is pathogenic (PMID: 22521436, 21637107). The phenotype of an individual heterozygous for this variant is highly specific for Glycogen Storage Disease II based on GAA activity consistent with disease (PMID: 21637107, 22521436). One additional variant at the same position, p.Tyr766Cys, has been reported as a VUS in ClinVar (Variation ID: 285197). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PM3, PM2, PP3, PP4 (Richards 2015).

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