ClinVar Miner

Submissions for variant NM_000152.5(GAA):c.725C>T (p.Ala242Val) (rs745861849)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000555802 SCV000626633 uncertain significance Glycogen storage disease, type II 2019-08-26 criteria provided, single submitter clinical testing This sequence change replaces alanine with valine at codon 242 of the GAA protein (p.Ala242Val). The alanine residue is moderately conserved and there is a small physicochemical difference between alanine and valine. This variant is present in population databases (rs745861849, ExAC 0.01%). This variant has been reported in an individual affected with glycogen storage disease (PMID: 18425781). Experimental studies have shown that this missense change has a mild effect on GAA activity (PMID: 18425781). In summary, this variant has uncertain impact on GAA function. The available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Integrated Genetics/Laboratory Corporation of America RCV000770759 SCV000695665 uncertain significance not specified 2019-02-20 criteria provided, single submitter clinical testing Variant summary: GAA c.725C>T (p.Ala242Val) results in a non-conservative amino acid change located in the Galactose mutarotase, N-terminal barrel domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 9.3e-05 in 246022 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in GAA causing Glycogen Storage Disease, Type 2 (Pompe Disease) (9.3e-05 vs 0.0042), allowing no conclusion about variant significance. c.725C>T has been reported in the literature in an affected individual (Kroos_2008). This report does not provide unequivocal conclusions about association of the variant with Glycogen Storage Disease, Type 2 (Pompe Disease). Experimental evidence evaluating an impact on protein function demonstrated a potentially mild effect on alpha-glucosidase activity (Kroos_2008). Three ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
Counsyl RCV000555802 SCV000800049 uncertain significance Glycogen storage disease, type II 2018-05-18 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000732877 SCV000860874 uncertain significance not provided 2018-04-18 criteria provided, single submitter clinical testing

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