ClinVar Miner

Submissions for variant NM_000152.5(GAA):c.2105G>A (p.Arg702His) (rs398123172)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000541873 SCV000796243 likely pathogenic Glycogen storage disease, type II 2017-12-07 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000489782 SCV000709614 likely pathogenic not provided 2017-06-27 criteria provided, single submitter clinical testing
GeneDx RCV000489782 SCV000576679 pathogenic not provided 2018-08-22 criteria provided, single submitter clinical testing The R702H variant has previously been reported in several unrelated patients with Pompe disease (Kroos et al., 2008; Qiu et al., 2007; Ding et al., 2015). The R702H variant is observed in 2/21,424 (0.009%) alleles from individuals of African background and 13/248,554 (0.005%) total alleles in large population cohorts (Lek et al., 2016). The R702H variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. However, this variant is located within the catalytic barrel domain (Sugawara et al., 2009). Functional analysis of R702H found that it is associated with significantly reduced but not absent enzyme activity compared to wild-type (Kroos et al., 2008). Another missense variant at the same postion (R702C) has been also reported in association with Pompe disease (Montalvo et al., 2004; Remiche et al., 2014). We interpret R702H as a pathogenic variant.
Integrated Genetics/Laboratory Corporation of America RCV000541873 SCV000695647 pathogenic Glycogen storage disease, type II 2017-08-21 criteria provided, single submitter clinical testing Variant summary: The GAA c.2105G>A (p.Arg702His) variant involves the alteration of a conserved nucleotide located in the Glycoside hydrolase superfamily domain of the protein (InterPro). 5/5 in silico tools predict a damaging outcome for this variant. This variant was found in 13/248554 control chromosomes in genomAD at a frequency of 0.0000523, which does not exceed the estimated maximal expected allele frequency of a pathogenic GAA variant (0.0042205). This variant has been reported in multiple Pompe pts. Functional study showed deficient enzyme activity, and variant was classified as a mild pathogenic mutation (Kroos_2008) . In addition, one other clinical diagnostic laboratory classified this variant as pathogenic. Variant involving the same codon Arg702Cys has been reported in affected individuals suggesting functional importance of this location. Taken together, this variant is classified as pathogenic.
Invitae RCV000541873 SCV000626543 pathogenic Glycogen storage disease, type II 2019-01-07 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 702 of the GAA protein (p.Arg702His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs398123172, ExAC 0.02%). This variant has been observed in several individuals affected with Pompe disease (PMID: 18211760, 26310554, 28394184). ClinVar contains an entry for this variant (Variation ID: 426278). Experimental studies have shown that this missense change has a deleterious effect on GAA activity (PMID: 18425781). This variant disrupts the p.Arg702 amino acid residue in GAA. Other variant(s) that disrupt this residue have been observed in affected individuals (PMID: 14972326, 24158270, 29122469, 27344650, 22252923), suggesting that it is a clinically significant residue. As a result, variants that disrupt this residue are likely to be causative of disease. For these reasons, this variant has been classified as Pathogenic.

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