ClinVar Miner

Submissions for variant NM_000152.5(GAA):c.1842G>A (p.Thr614=)

gnomAD frequency: 0.00003  dbSNP: rs373955374
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Eurofins NTD LLC (GA) RCV000726353 SCV000344023 uncertain significance not provided 2016-08-01 criteria provided, single submitter clinical testing
GeneDx RCV000726353 SCV000718376 likely benign not provided 2018-10-03 criteria provided, single submitter clinical testing
Invitae RCV000631085 SCV000752078 uncertain significance Glycogen storage disease, type II 2019-10-31 criteria provided, single submitter clinical testing This sequence change affects codon 614 of the GAA mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the GAA protein. This variant is present in population databases (rs373955374, ExAC 0.01%). This variant has not been reported in the literature in individuals with GAA-related disease. ClinVar contains an entry for this variant (Variation ID: 289635). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Broad Institute Rare Disease Group, Broad Institute RCV000631085 SCV001422618 likely benign Glycogen storage disease, type II 2020-01-22 criteria provided, single submitter curation The c.1842G>A (p.Thr614=) 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 Invitae and a likely benign variant by GeneDx in ClinVar (Variation ID: 289635). This variant has been identified in 0.013% (3/23922) of African chromosomes by the Genome Aggregation Database (gnomAD,; dbSNP rs373955374). 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).
Genome-Nilou Lab RCV000631085 SCV001810630 uncertain significance Glycogen storage disease, type II 2021-07-22 criteria provided, single submitter clinical testing

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