ClinVar Miner

Submissions for variant NM_000152.5(GAA):c.2015G>A (p.Arg672Gln) (rs778418246)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000410731 SCV000486623 likely pathogenic Glycogen storage disease, type II 2016-07-08 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000410731 SCV000917384 pathogenic Glycogen storage disease, type II 2017-09-28 criteria provided, single submitter clinical testing Variant summary: The GAA c.2015G>A (p.Arg672Gln) variant involves the alteration of a conserved nucleotide. 4/5 in silico tools predict a damaging outcome for this variant. This variant was found in 5/237400 control chromosomes at a frequency of 0.0000211, which does not exceed the estimated maximal expected allele frequency of a pathogenic GAA variant (0.0042205). The variant has been reported in affected individuals in the literature in the homozygous and compound heterozygous state, and has been reported in homozygous patients to lead to complete loss of acid maltase activity (Tsujino_GAA_ND_2000). In addition, one clinical diagnostic laboratory/reputable database classified this variant as likely pathogenic. Taken together, this variant is classified as pathogenic.
Invitae RCV000410731 SCV000939597 pathogenic Glycogen storage disease, type II 2020-10-08 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 672 of the GAA protein (p.Arg672Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs778418246, ExAC 0.01%). This variant has been observed in individuals affected with Pompe disease, including individuals with low alpha-glucosidase enzyme activity (less than 40% of normal), findings that are highly specific for this disease (PMID: 23884227, 11053688, 28592009, 25712382). This variant has been reported in an individual affected with inherited muscular disorder (PMID: 27363342). ClinVar contains an entry for this variant (Variation ID: 371126). Experimental studies have shown that this missense change results in severely reduced alpha-glucosidase enzyme activity (PMID: 9535769, 19862843, 28592009). 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. This variant disrupts the p.Arg672 amino acid residue in GAA. Other variant(s) that disrupt this residue have been observed in affected individuals (PMID: 9535769, 21484825, 21757382, 15986226, 16917947, 19862843), 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.
Broad Institute Rare Disease Group, Broad Institute RCV000410731 SCV001422656 pathogenic Glycogen storage disease, type II 2020-01-22 no assertion criteria provided curation The p.Arg672Gln variant in GAA has been reported in 7 individuals (including 4 Japanese and 1 Korean individuals) with Glycogen Storage Disease II, segregated with disease in 4 affected relatives from 2 families (PMID: 17092519, 11053688, 9535769, 25712382), and has also been reported likely pathogenic by Counsyl in ClinVar (Variation ID: 371126). This variant has been identified in 0.011% (2/18064) of East Asian chromosomes, 0.003% (1/29862) of South Asian chromosomes, and 0.001% (1/108950) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD,; dbSNP rs778418246). 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.Arg672Gln variant may impact GAA activity (PMID: 9535769, 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 and activate a cryptic splice site, though this information is not predictive enough to determine pathogenicity. The presence of this variant in combination with a reported likely pathogenic variant, and in an individual with Glycogen Storage Disease II increases the likelihood that the p.Arg672Gln variant is pathogenic (PMID: 17092519). The presence of this variant in the homozygous state in 4 individuals with Glycogen Storage Disease II also increases the likelihood that the p.Arg672Gln variant is pathogenic (PMID: 11053688, 9535769, 25712382). The phenotype of 4 individuals with this variant (including 2 homozygotes) is highly specific for Glycogen Storage Disease II based on assays that only detected residual GAA enzyme activity in muscle biopsy and/or cultured skin fibroblast cells (PMID: 11053688). One additional pathogenic variant at the the same position, p.Arg672Trp, has been curated by our study, supporting that a change at this position may not be tolerated. 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 and multiple occurrences in the homozygous state and the heterozygous state with a pathogenic variant in individuals with Glycogen Storage Disease II. ACMG/AMP Criteria applied: PM3_Strong, PS3, PM2, PM5, PP3, PP4 (Richards 2015).

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