ClinVar Miner

Submissions for variant NM_000152.5(GAA):c.726G>A (p.Ala242=) (rs148578399)

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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 RCV000675220 SCV000338356 uncertain significance not provided 2018-01-18 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000315968 SCV000407269 uncertain significance Glycogen storage disease, type II 2018-01-13 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
GeneDx RCV000307971 SCV000526123 likely benign not specified 2018-01-19 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 RCV000315968 SCV000626634 benign Glycogen storage disease, type II 2019-12-31 criteria provided, single submitter clinical testing
Mayo Clinic Genetic Testing Laboratories,Mayo Clinic RCV000675220 SCV000800865 likely benign not provided 2015-12-16 no assertion criteria provided clinical testing
Broad Institute Rare Disease Group,Broad Institute RCV000315968 SCV001423083 likely benign Glycogen storage disease, type II 2020-01-22 no assertion criteria provided curation The c.726G>A (p.Ala242=) variant in GAA has not been previously reported in individuals with Glycogen Storage Disease II but has been reported as a VUS (by EGL and Illumina), a likely benign variant (by GeneDx and Mayo Clinic Genetic Testing Laboratories), and a benign variant (by Invitae) in ClinVar (Variation ID: 285366). This variant has been identified in 0.2769% (69/24916) of African chromosomes, including 1 homozygote, and 0.04516% (16/35432) of Latino chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs148578399). 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: BP4, BP7 (Richards 2015).

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