ClinVar Miner

Submissions for variant NM_000152.5(GAA):c.2190-4G>A (rs759974338)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001083210 SCV000626550 likely benign Glycogen storage disease, type II 2019-12-31 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000588046 SCV000695650 uncertain significance not provided 2016-02-22 criteria provided, single submitter clinical testing Variant summary: c.2190-4G>A affects a non-conserved nucleotide, resulting in an intronic change. Mutation Taster predicts for a benign outcome. 5/5 programs via Alamut predict that this variant does not affect normal splicing. ESEfinder predicts changes of binding motifs for RNA splicing enhancers. This variant was found in 4/120722 control chromosomes at a frequency of 0.0000331, which does not exceed the maximal expected frequency of a pathogenic allele (0.0042205) in this gene. The variant of interest has not been reported in affected individuals via publications and/or reputable databases/clinical laboratories, nor evaluated for functional impact by in vivo/vitro studies. Because of the absence of clinical information and the lack of functional studies, the variant has been classified as a variant of uncertain significance (VUS) until additional information becomes available.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000588046 SCV000702692 uncertain significance not provided 2016-11-02 criteria provided, single submitter clinical testing
GeneDx RCV000597544 SCV000722619 likely benign not specified 2017-09-05 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.
Broad Institute Rare Disease Group,Broad Institute RCV001083210 SCV001422811 likely benign Glycogen storage disease, type II 2020-01-22 no assertion criteria provided curation The c.2190-4G>A variant in GAA has not been previously reported in individuals with Glycogen Storage Disease II but has been reported as a VUS (by Integrated Genetics and EGL Genetic Diagnostics) and a likely benign variant (by GeneDx and Invitae) in ClinVar (Variation ID: 456393). This variant has been identified in 0.02982% (3/10062) of Ashkenazi Jewish chromosomes and 0.02603% (9/34578) of Latino chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs759974338). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. This variant is located in the 3' plice region. Computational prediction tools, including splice predictors, and conservation analyses suggest that this variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. 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, BP7, BP4 (Richards 2015).

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