ClinVar Miner

Submissions for variant NM_000152.5(GAA):c.1438-1G>C (rs147804176)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000169615 SCV000221141 likely pathogenic Glycogen storage disease, type II 2015-02-18 criteria provided, single submitter literature only
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000727411 SCV000708298 pathogenic not provided 2017-05-02 criteria provided, single submitter clinical testing
Invitae RCV000169615 SCV000948372 pathogenic Glycogen storage disease, type II 2018-10-01 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 9 of the GAA gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals affected with infantile-onset and adult-onset autosomal recessive Pompe disease (PMID:29122469, 25455803, 22538254, 24495340). This variant is also known as IVS9-1G>C in the literature. ClinVar contains an entry for this variant (Variation ID: 189184). Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in GAA are known to be pathogenic (PMID: 18425781, 22252923). For these reasons, this variant has been classified as Pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000169615 SCV001338646 pathogenic Glycogen storage disease, type II 2020-04-20 criteria provided, single submitter clinical testing Variant summary: GAA c.1438-1G>C is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a 3' acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 250786 control chromosomes. c.1438-1G>C has been reported in the literature in individuals affected with Glycogen Storage Disease, Type 2 (Pompe Disease- examples Raben_2002, Prater_2012, Katona_2014, Vill_2015). These data indicate that the variant is likely to be associated with disease. To our knowledge, there is no experimental evidence evaluating an impact on protein function reported in the literature. Three other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

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