Submissions for variant NM_000152.5(GAA):c.2228A>G (p.Gln743Arg)

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Total submissions: 5

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Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001193011	SCV001361533	pathogenic	Glycogen storage disease, type II	2022-06-20	criteria provided, single submitter	clinical testing	Variant summary: GAA c.2228A>G (p.Gln743Arg) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250916 control chromosomes (gnomAD), but has been reported in the literature in compound heterozygous individuals affected with Glycogen Storage Disease, Type 2 (Pompe Disease) (Dlamini_2008, Kroos_2008, Preisler_2013, Vaeggemose_2021). These data indicate that the variant may be associated with disease. At least one publication reported experimental evidence evaluating an impact on protein function, and demonstrated that the variant caused a significant decrease in protein levels and in enzymatic activity (Kroos_2012). The most pronounced variant effect results in <10% of normal activity. Another clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae	RCV001193011	SCV003443321	likely pathogenic	Glycogen storage disease, type II	2023-11-02	criteria provided, single submitter	clinical testing	This sequence change replaces glutamine, which is neutral and polar, with arginine, which is basic and polar, at codon 743 of the GAA protein (p.Gln743Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with Pompe disease (PMID: 18434155, 24011652). ClinVar contains an entry for this variant (Variation ID: 561162). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt GAA protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects GAA function (PMID: 22644586). 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.
Revvity Omics, Revvity	RCV003144478	SCV003833865	likely pathogenic	not provided	2022-12-20	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV001193011	SCV004195470	likely pathogenic	Glycogen storage disease, type II	2023-09-27	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV001193011	SCV002092115	likely pathogenic	Glycogen storage disease, type II	2021-04-20	no assertion criteria provided	clinical testing

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