ClinVar Miner

Submissions for variant NM_000152.5(GAA):c.1075+9T>C (rs751918816)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000726676 SCV000345924 uncertain significance not provided 2016-09-15 criteria provided, single submitter clinical testing
GeneDx RCV000285215 SCV000725024 likely benign not specified 2017-12-07 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.
Invitae RCV001087978 SCV001031414 likely benign Glycogen storage disease, type II 2019-12-31 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000285215 SCV001338213 uncertain significance not specified 2020-02-24 criteria provided, single submitter clinical testing Variant summary: GAA c.1075+9T>C 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. 4/4 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 2.4e-05 in 250638 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.1075+9T>C in individuals affected with Glycogen Storage Disease, Type 2 (Pompe Disease) and no experimental evidence demonstrating its impact on protein function have been reported. Three ClinVar submitters (evaluation after 2014) cite the variant as likely benign (n=2) or uncertain significance (n=1). Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
Broad Institute Rare Disease Group,Broad Institute RCV001087978 SCV001423064 likely benign Glycogen storage disease, type II 2020-01-22 no assertion criteria provided curation The c.1075+9T>C 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 in ClinVar (Variation ID: 291212). This variant has been identified in 0.006% (8/128520) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs751918816). 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 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: PM2, BP4, BP7 (Richards 2015).

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