ClinVar Miner

Submissions for variant NM_000152.5(GAA):c.1123C>T (p.Arg375Cys) (rs372486238)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000372718 SCV000344735 uncertain significance not provided 2017-05-05 criteria provided, single submitter clinical testing
Invitae RCV000537433 SCV000626494 uncertain significance Glycogen storage disease, type II 2019-12-04 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 375 of the GAA protein (p.Arg375Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs372486238, ExAC 0.02%). This variant has not been reported in the literature in individuals with GAA-related disease. ClinVar contains an entry for this variant (Variation ID: 290225). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). A different missense substitution at this codon (p.Arg375Leu) has been determined to be pathogenic (PMID: 24158270, 18429042, 22990675) and another missense substitution (p.Arg375His) has been reported in individuals affected with Pompe disease (PMID: 21484825, 21757382). This suggests that the arginine residue is critical for GAA protein function and that other missense substitutions at this position may also be pathogenic. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Integrated Genetics/Laboratory Corporation of America RCV000780270 SCV000917396 uncertain significance not specified 2018-10-08 criteria provided, single submitter clinical testing Variant summary: GAA c.1123C>T (p.Arg375Cys) results in a non-conservative amino acid change located in the Glycoside hydrolase superfamily of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-05 in 275242 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in GAA causing Glycogen Storage Disease, Type 2 (Pompe Disease) (4e-05 vs 0.0042), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.1123C>T in individuals affected with Glycogen Storage Disease, Type 2 (Pompe Disease) and no experimental evidence demonstrating its impact on protein function have been reported. Two 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 uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

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