ClinVar Miner

Submissions for variant NM_000152.5(GAA):c.1843G>A (p.Gly615Arg) (rs549029029)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000169115 SCV000220317 likely pathogenic Glycogen storage disease, type II 2014-05-14 criteria provided, single submitter literature only
Invitae RCV000169115 SCV000824487 pathogenic Glycogen storage disease, type II 2019-12-01 criteria provided, single submitter clinical testing This sequence change replaces glycine with arginine at codon 615 of the GAA protein (p.Gly615Arg). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and arginine. This variant is present in population databases (rs549029029, ExAC 0.03%). This variant has been observed to be homozygous, or in combination with another GAA variant, in several individuals affected with Pompe disease (PMID: 15366815, 10338092, 16860134, 18607768, 18458862, 21757382, 24269976, 25037089). ClinVar contains an entry for this variant (Variation ID: 188786). Experimental studies have shown that this missense change leads to reduced GAA activity in vitro (PMID: 19862843). For these reasons, this variant has been classified as Pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000169115 SCV000919384 pathogenic Glycogen storage disease, type II 2018-07-05 criteria provided, single submitter clinical testing Variant summary: GAA c.1843G>A (p.Gly615Arg) results in a non-conservative amino acid change in 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 2.1e-05 in 97298 control chromosomes (gnomAD and publication). The variant, c.1843G>A, has been reported in the literature in individuals affected with Glycogen Storage Disease, Type 2 (Pompe Disease), whom presented with significantly decreased enzyme activity (<10%). These data indicate that the variant is likely to be associated with disease. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic.
Broad Institute Rare Disease Group,Broad Institute RCV000169115 SCV001422905 pathogenic Glycogen storage disease, type II 2020-01-22 no assertion criteria provided curation The p.Gly615Arg variant in GAA has been reported in 13 individuals (including 4 Taiwanese, 1 Chinese, and 1 German individuals) with Glycogen Storage Disease II, segregated with disease in 2 affected relatives from 1 family (PMID: 16860134, 18458862, 10338092, 24269976, 21232767, 20080426, 15366815, 18607768, 21757382, 25037089), and has also been reported likely pathogenic by Counsyl and pathogenic by Invitae and Integrated Genetics in ClinVar (Variation ID: 188786). This variant has been identified in 0.022% (4/17994) of East Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs549029029). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. In vitro functional studies provide some evidence that the p.Gly615Arg variant may impact protein function (PMID: 19862843). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. The presence of this variant in combination with reported pathogenic variants in individuals with Glycogen Storage Disease II increases the likelihood that the p.Gly615Arg variant is pathogenic (PMID: 16860134, 18458862). The phenotype of individuals heterozygous for this variant is highly specific for Glycogen Storage Disease II based on reduced GAA activity in relevant tissues, consistent with disease (PMID: 21757382, 16860134, 18458862). In summary, this variant meets criteria to be classified as pathogenic for Glycogen Storage Disease II in an autosomal recessive manner based on in vitro functional studies, low frequency in the general population, and multiple occurrences in combination with pathogenic variants in affected individuals. ACMG/AMP Criteria applied: PS3, PM2, PM3, PP3, PP4 (Richards 2015).

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