ClinVar Miner

Submissions for variant NM_000152.5(GAA):c.2332-12A>T (rs200965268)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000723547 SCV000110008 uncertain significance not provided 2012-09-10 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000244544 SCV000302677 likely benign not specified criteria provided, single submitter clinical testing
GeneDx RCV000244544 SCV000530270 likely benign not specified 2017-08-31 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000244544 SCV001361266 likely benign not specified 2019-04-11 criteria provided, single submitter clinical testing Variant summary: GAA c.2332-12A>T alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00055 in 274190 control chromosomes, predominantly at a frequency of 0.0058 within the African subpopulation in the gnomAD database. The observed variant frequency within African control individuals in the gnomAD database is approximately 1.37 fold of the estimated maximal expected allele frequency for a pathogenic variant in GAA causing Glycogen Storage Disease, Type 2 (Pompe Disease) phenotype (0.0042), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African origin. To our knowledge, no occurrence of c.2332-12A>T in individuals affected with Glycogen Storage Disease, Type 2 (Pompe Disease) and no experimental evidence demonstrating its impact on protein function have been reported. A ClinVar submission from a clinical diagnostic laboratory (evaluation after 2014) cites the variant as likely benign. Based on the evidence outlined above, the variant was classified as likely benign.
Invitae RCV001248964 SCV001731834 benign Glycogen storage disease, type II 2020-10-07 criteria provided, single submitter clinical testing
Broad Institute Rare Disease Group, Broad Institute RCV001248964 SCV001422770 likely benign Glycogen storage disease, type II 2020-01-22 no assertion criteria provided curation The c.2332-12A>T variant in GAA has not been previously reported in individuals with Glycogen Storage Disease II but has been reported as a VUS by EGL Genetic Diagnostics and a likely benign variant by GeneDx and PreventionGenetics in ClinVar (Variation ID: 92475). This variant has been identified in 0.573% (142/24770) of African chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs200965268). This variant has been seen in the general population at a greater frequency than expected for Glycogen Storage Disease II and is consistent with a benign role. Computational prediction tools and conservation analyses suggest that this variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. However, novel synonymous variants supported by computational evidence without raised suspicion for an impact are likely benign (Richards 2015). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely benign. ACMG/AMP Criteria applied: BS1, BP4, BP7 (Richards 2015).

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