ClinVar Miner

Submissions for variant NM_000152.5(GAA):c.2152G>A (p.Val718Ile) (rs141017311)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000675239 SCV000331842 uncertain significance not provided 2018-03-29 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000382817 SCV000407293 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 RCV000265982 SCV000518838 likely benign not specified 2017-04-20 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 RCV000382817 SCV000626547 likely benign Glycogen storage disease, type II 2020-11-25 criteria provided, single submitter clinical testing
Center for Advanced Laboratory Medicine, UC San Diego Health,University of California San Diego RCV000852733 SCV000995448 likely benign Hypertrophic cardiomyopathy 2017-06-19 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000675239 SCV001151431 uncertain significance not provided 2019-05-01 criteria provided, single submitter clinical testing
Mayo Clinic Laboratories, Mayo Clinic RCV000675239 SCV000800885 likely benign not provided 2017-05-10 no assertion criteria provided clinical testing
Broad Institute Rare Disease Group, Broad Institute RCV000382817 SCV001423078 benign Glycogen storage disease, type II 2020-01-22 no assertion criteria provided curation The p.Val718Ile variant in GAA has not been previously reported in individuals with Glycogen Storage Disease II but has been reported as a VUS (by EGL, Illumina, and Invitae) and a likely benign variant (by GeneDx and Mayo Clinic Genetic Testing Laboratories) in ClinVar (Variation ID: 281232). This variant has been identified in 0.533% (51/9570) of Ashkenazi Jewish chromosomes, 0.011% (3/27108) of South Asian chromosomes and 0.007% (8/112166) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs141017311). 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. In vitro functional studies provide some evidence that the p.Val718Ile variant may have no impact on GAA activity or protein levels (PMID: 22644586). However, these types of assays may not accurately represent biological function. 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. In summary, this variant meets criteria to be classified as benign for Glycogen Storage Disease II in an autosomal recessive manner based on its frequency in the general population and well-established functional studies. ACMG/AMP Criteria applied: BS3, BS1, BP4 (Richards 2015).
Natera, Inc. RCV000382817 SCV001459749 likely benign Glycogen storage disease, type II 2020-09-16 no assertion criteria provided clinical testing

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