ClinVar Miner

Submissions for variant NM_000152.5(GAA):c.266G>A (p.Arg89His) (rs200586324)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000370905 SCV000335191 uncertain significance not provided 2016-09-13 criteria provided, single submitter clinical testing
Invitae RCV000547185 SCV000626592 uncertain significance Glycogen storage disease, type II 2019-11-20 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 89 of the GAA protein (p.Arg89His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs200586324, ExAC 0.01%). This variant has been reported in several individuals affected with Pompe disease (PMID: 22644586, 25626711, 28600779). ClinVar contains an entry for this variant (Variation ID: 283219). Experimental studies have found that this missense change does not impact GAA function (PMID: 22644586). 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.
Illumina Clinical Services Laboratory,Illumina RCV000547185 SCV001287672 uncertain significance Glycogen storage disease, type II 2017-04-27 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Centogene AG - the Rare Disease Company RCV000547185 SCV001426579 pathogenic Glycogen storage disease, type II criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000370905 SCV001500155 pathogenic not provided 2020-09-01 criteria provided, single submitter clinical testing
GeneDx RCV000370905 SCV001767424 uncertain significance not provided 2021-05-26 criteria provided, single submitter clinical testing Reported in the homozygous state in the presence of an additional homozygous GAA variant (c.-32-13T>G, a common pathogenic variant in individuals with adult-onset GSDII) in an infant severely affected with GSDII; functional studies indicated only minimally reduced enzyme activity and the R89H variant was classified as presumably non-pathogenic by the authors (Kroos M et al., 2012); Reported in the homozygous state in a patient with a dual diagnosis of GSDII and GSDI who also harbored a homozgyous pathogenic variant in the G6PC gene (Monies D et al., 2017); Reported in additional patients with GSDII with either a variant of uncertain significance in trans or for whom a second variant was not identified (Hahn A et al., 2015; Nair P et al., 2018; Bertoli-Avella AM et al., 2021); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Reported in ClinVar (ClinVar Variant ID# 283219; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 28600779, 27927596, 22644586, 32860008, 33202836, 31342611, 30293248, 25626711)
Nilou-Genome Lab RCV000547185 SCV001810207 likely pathogenic Glycogen storage disease, type II 2021-07-22 criteria provided, single submitter clinical testing
Broad Institute Rare Disease Group, Broad Institute RCV000547185 SCV001422661 uncertain significance Glycogen storage disease, type II 2020-01-22 no assertion criteria provided curation The p.Arg89His variant in GAA has been reported in 3 individuals with Glycogen Storage Disease II (PMID: 22644586, 28600779, 25626711), but it is unclear whether this variant causes Glycogen Storage Disease II. This variant has also been reported as a VUS by Invitae and EGL Genetic Diagnostics in ClinVar (Variation ID: 283219), and has been identified in 0.117% (12/10272) of Ashkenazi Jewish chromosomes, 0.016% (5/30550) of South Asian chromosomes, and 0.015% (19/127034) of European (Non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs200586324). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. One individual was homozygous for this variant and another reported pathogenic variant for Glycogen Storage Disease I in G6PC, p.Arg83Cys (PMID: 28600779; Variation ID: 11998). Another individual was homozygous for this variant and another VUS reported in the literature, c.546+45G>C (PMID: 22644586). This variant was also seen in trans with a rare VUS in GAA (PMID: 25626711). In vitro functional studies provide some evidence that the p.Arg89His variant may not impact protein function (PMID: 22644586). 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. In summary, while the clinical significance of the p.Arg89His variant is uncertain, these data suggest that it is more likely to be benign. ACMG/AMP Criteria applied: PP3, BS3_Supporting, BP2 (Richards 2015).
Natera, Inc. RCV000547185 SCV001453580 uncertain significance Glycogen storage disease, type II 2020-09-16 no assertion criteria provided clinical testing

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