ClinVar Miner

Submissions for variant NM_000152.5(GAA):c.1552-13G>A (rs111261964)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
PreventionGenetics,PreventionGenetics RCV000246280 SCV000302663 likely benign not specified criteria provided, single submitter clinical testing
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000246280 SCV000338203 likely benign not specified 2015-12-16 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000392826 SCV000407282 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 RCV000246280 SCV000724576 likely benign not specified 2017-10-18 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 RCV000246280 SCV000917387 likely benign not specified 2018-01-25 criteria provided, single submitter clinical testing Variant summary: The GAA c.1552-13G>A variant involves the alteration of a non-conserved intronic nucleotide. One in silico tool predicts a benign outcome for this variant. 5/5 splice prediction tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. This variant was found in 788/277130 control chromosomes (2 homozygotes), predominantly observed in the European (Non-Finnish) subpopulation at a frequency of 0.004675 (592/126628)(gnomAD). This frequency is slightly above the estimated maximal expected allele frequency of a pathogenic GAA variant (0.0042205), suggesting this is likely a benign polymorphism found primarily in the populations of European (Non-Finnish) origin. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as likely benign and one other lab classified it as VUS. Taken together, this variant is classified as likely benign.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000392826 SCV001471012 likely benign Glycogen storage disease, type II 2019-12-14 criteria provided, single submitter clinical testing
Invitae RCV000392826 SCV001731733 benign Glycogen storage disease, type II 2020-11-24 criteria provided, single submitter clinical testing
Stanford Center for Inherited Cardiovascular Disease, Stanford University RCV000786312 SCV000925081 uncertain significance not provided 2011-02-17 no assertion criteria provided provider interpretation
Broad Institute Rare Disease Group, Broad Institute RCV000392826 SCV001423080 likely benign Glycogen storage disease, type II 2020-01-22 no assertion criteria provided curation The c.1552-13G>A variant in GAA has not been previously reported in individuals with Glycogen Storage Disease II but has been reported as a likely benign variant (by GeneDx, EGL, and Prevention Genetics) and as a VUS (by Illumina) in ClinVar (Variation ID: 255353). This variant has been identified in 0.4705% (607/129008) of European (non-Finnish) chromosomes, including 2 homozygotes, by the Genome Aggregation Database (gnomAD,; dbSNP rs111261964). Although this variant has been seen in the general population, its frequency is not high enough to rule out a pathogenic 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 (PMID: 25741868). 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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