ClinVar Miner

Submissions for variant NM_000152.5(GAA):c.1942G>A (p.Gly648Ser) (rs536906561)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000169262 SCV000220552 likely pathogenic Glycogen storage disease, type II 2014-07-24 criteria provided, single submitter literature only
Invitae RCV000169262 SCV000626535 pathogenic Glycogen storage disease, type II 2019-12-30 criteria provided, single submitter clinical testing This sequence change replaces glycine with serine at codon 648 of the GAA protein (p.Gly648Ser). The glycine residue is highly conserved and there is a small physicochemical difference between glycine and serine. This variant is present in population databases (rs536906561, ExAC 0.05%). This variant has been reported in combination with another GAA variant in individuals affected with glycogen storage disease type II (Pompe disease) (PMID: 9535769, 17643989, 26575883), including the finding of this variant on the opposite chromosome (in trans) from a pathogenic variant. This finding is consistent with autosomal recessive inheritance, and suggests that this variant contributes to disease. ClinVar contains an entry for this variant (Variation ID: 188902). Experimental studies have shown that this missense change causes a severe reduction in GAA enzyme activity (PMID: 9535769, 19862843). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. A different missense substitution at this codon (p.Gly648Asp) has been reported in an individual affected with Pompe disease (PMID: 23146291, 22644586). For these reasons, this variant has been classified as Pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000169262 SCV001361272 pathogenic Glycogen storage disease, type II 2019-01-07 criteria provided, single submitter clinical testing Variant summary: GAA c.1942G>A (p.Gly648Ser) results in a non-conservative amino acid change in the Glycoside hydrolase superfamily (IPR017853) 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 5.5e-05 in 237998 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in GAA causing Glycogen Storage Disease, Type 2 (Pompe Disease) (5.5e-05 vs 0.0042), allowing no conclusion about variant significance. c.1942G>A has been reported in the literature in multiple individuals affected with adult onset and infantile onset Glycogen Storage Disease, Type 2 (Pompe Disease)(Huie_1998, Elenga_2018). A patient diagnosed with adult onset Pompe Disease was observed to have <10% enzyme activity in vivo. A ClinVar submission from a clinical diagnostic laboratory (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

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