ClinVar Miner

Submissions for variant NM_000152.5(GAA):c.1552-3C>G (rs375470378)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000593914 SCV000792707 likely pathogenic Glycogen storage disease, type II 2017-07-21 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000479616 SCV000701459 likely pathogenic not provided 2017-03-16 criteria provided, single submitter clinical testing
GeneDx RCV000479616 SCV000567714 pathogenic not provided 2015-09-01 criteria provided, single submitter clinical testing The c.1552-3 C>G variant has been previously reported as a homozygous variant in a patient with a mild form of GSDII (Kroos et al., 2006). Functional studies demonstrate that the c.1552-3 C>G variantcauses aberrant gene splicing and results in reduced enzyme activity (Kroos et al., 2006; Bergsma et al., 2015). It was not observed with any significant frequency in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project.Therefore, we interpret c.1552-3 C>G as a pathogenic variant.
Integrated Genetics/Laboratory Corporation of America RCV000593914 SCV000917383 pathogenic Glycogen storage disease, type II 2017-11-06 criteria provided, single submitter clinical testing Variant summary: The GAA c.1552-3C>G variant involves the alteration of a non-conserved intronic nucleotide and 5/5 splice prediction tools predict an impact on normal splicing. Multiple functional studies support these predictions with findings indicating that the variant does affect splicing (Kroos_2006, Bergsma_2015). This variant was found in 38/277142 control chromosomes, predominantly observed in the European (Non-Finnish) subpopulation at a frequency of 0.000276 (35/126638), which does not exceed the estimated maximal expected allele frequency of a pathogenic GAA variant (0.0042205). Multiple publications have cited the variant in homozygous affected individuals. In addition, a clinical diagnostic laboratory classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Invitae RCV000593914 SCV000819326 likely pathogenic Glycogen storage disease, type II 2018-09-27 criteria provided, single submitter clinical testing This sequence change falls in intron 10 of the GAA gene. It does not directly change the encoded amino acid sequence of the GAA protein, but it affects a nucleotide within the consensus splice site of the intron. This variant is present in population databases (rs375470378, ExAC 0.02%). This variant has been observed as homozygous in individuals with low alpha-glucosidase enzyme activity, a finding that is highly specific for glycogen storage disease (PMID: 25243733, 16838077, 28196920, 23430949, Invitae). ClinVar contains an entry for this variant (Variation ID: 419722). Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Experimental studies have shown that this intronic change results in an aberrantly spliced GAA primary transcript (PMID: 16838077, 25243733). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

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