ClinVar Miner

Submissions for variant NM_000152.5(GAA):c.2297A>G (p.Tyr766Cys) (rs144016984)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000403113 SCV000338123 uncertain significance not provided 2016-01-04 criteria provided, single submitter clinical testing
Invitae RCV001049848 SCV001213921 pathogenic Glycogen storage disease, type II 2020-10-16 criteria provided, single submitter clinical testing This sequence change replaces tyrosine with cysteine at codon 766 of the GAA protein (p.Tyr766Cys). The tyrosine residue is highly conserved and there is a large physicochemical difference between tyrosine and cysteine. This variant is present in population databases (rs144016984, ExAC 0.006%). This variant has been observed in several individuals affected with Pompe disease (PMID: 21605996, 22538254, 30564623). ClinVar contains an entry for this variant (Variation ID: 285197). 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: 28394184, 22538254), suggesting that it is a clinically significant residue. As a result, variants that disrupt this residue are likely to be causative of disease. For these reasons, this variant has been classified as Pathogenic.
Illumina Clinical Services Laboratory,Illumina RCV001049848 SCV001281478 uncertain significance Glycogen storage disease, type II 2017-04-28 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001049848 SCV001442688 likely pathogenic Glycogen storage disease, type II 2020-10-13 criteria provided, single submitter clinical testing Variant summary: GAA c.2297A>G (p.Tyr766Cys) 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 2.4e-05 in 250124 control chromosomes (gnomAD). c.2297A>G has been reported in the literature in individuals affected with Glycogen Storage Disease, Type 2 (Pompe Disease) (e.g. El-Gharbawy_2011, Herzog_2012, Fukuhara_2018, Nallamilli_2018). These data indicate that the variant may be associated with disease. Experimental evidence indicated GAA activity to be <10% in compound heterozygous patients with the variant (El-Gharbawy_2011, Herzog_2012, Fukuhara_2018). Two ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance and two ClinVar submitters (evaluation after 2014) cite it as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
GeneDx RCV000403113 SCV001796063 likely pathogenic not provided 2021-06-30 criteria provided, single submitter clinical testing Not observed at a significant frequency in large population cohorts (Lek et al., 2016); Reported in ClinVar but additional evidence is not available (ClinVar Variant ID #285197; Landrum et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 33073003, 21605996, 22676651, 27535533, 29124014, 30564623)
Nilou-Genome Lab RCV001049848 SCV001810186 likely pathogenic Glycogen storage disease, type II 2021-07-22 criteria provided, single submitter clinical testing
Broad Institute Rare Disease Group, Broad Institute RCV001049848 SCV001422964 likely pathogenic Glycogen storage disease, type II 2020-01-22 no assertion criteria provided curation The p.Tyr766Cys variant in GAA has been reported in at least two individuals with glycogen storage disease II (PMID: 22676651, 21605996, 29124014) and has been identified in 0.007% (2/30610) of South Asian chromosomes and 0.004% (5/128266) of European (non-Finnish) 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. This variant has also been reported in ClinVar (VariationID: 285197) as a VUS by EGL Genetics Diagnostics. One additional likely pathogenic variant, resulting in a different amino acid change at the same position, p.Tyr766Ser, has been reported in association with disease in ClinVar, slightly supporting that a change at this position may not be tolerated (Variation ID: 420102). The phenotype of individuals heterozygous for this variant is highly specific for glycogen storage disease II based on GAA enzyme activity being <10% of wild type, consistent with disease (PMID: 22676651, 21605996, 29124014). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. Additionally, the presence of this variant in combination with reported likely pathogenic variants c.1561G>A (VariationID: 4022; PMID: 22676651, 21605996) and p.Arg437Cys (VariationID:189082, PMID: 29124014) and in individuals with glycogen storage disease II increases the likelihood that the p.Tyr766Cys variant is pathogenic. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PM2, PP3, PM5_supporting, PP4, PM3_supporting (Richards 2015).

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