ClinVar Miner

Submissions for variant NM_000152.5(GAA):c.1286A>G (p.Gln429Arg) (rs200294882)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel, ClinGen RCV000528796 SCV001371699 benign Glycogen storage disease, type II 2020-01-22 reviewed by expert panel curation The highest continental population minor allele frequency for c.1286A>G (p.Gln429Arg) in gnomAD v2.1.1 is 0.01028 in the East Asian population. This is higher than the ClinGen LSD VCEP's BA1 threshold (>0.01), therefore meeting the BA1 criterion. There is a ClinVar entry for this variant (Variation ID: 284497; 2 star review status) with three submitters classifying the variant as benign and one as likely benign. In summary, this variant meets the criteria to be classified as benign for Pompe disease. GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen LSD VCEP: BA1.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000346911 SCV000337146 benign not specified 2015-11-12 criteria provided, single submitter clinical testing
GeneDx RCV000346911 SCV000519877 likely benign not specified 2016-08-23 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Invitae RCV000528796 SCV000626502 benign Glycogen storage disease, type II 2020-12-06 criteria provided, single submitter clinical testing
Center for Advanced Laboratory Medicine, UC San Diego Health,University of California San Diego RCV000852731 SCV000995446 benign Cardiomyopathy 2017-03-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000528796 SCV001281356 uncertain significance Glycogen storage disease, type II 2017-05-05 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000346911 SCV001361535 benign not specified 2019-08-09 criteria provided, single submitter clinical testing Variant summary: GAA c.1286A>G (p.Gln429Arg) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0008 in 234302 control chromosomes, predominantly at a frequency of 0.011 within the East Asian subpopulation in the gnomAD database, including 1 homozygote. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 2.6 fold of the estimated maximal expected allele frequency for a pathogenic variant in GAA causing Glycogen Storage Disease, Type 2 (Pompe Disease) phenotype (0.0042). In addition, the variant was also found in Japanese healthy controls with a frequency of 0.005, including 1 homozygote (in the HGVD database). These data strongly suggest that the variant is a benign polymorphism found primarily in populations of East Asian origin. The variant, c.1286A>G, has been reported in the literature in a newborn affected with infantile-onset Glycogen Storage Disease, Type 2 (Pompe Disease), however, this patient also carried two other pathogenic GAA variants, in cis (c.1062 C>G (p.Tyr354X)), and trans (c.1935C>A (p.Asp645Glu)) that could explain the phenotype, therefore supporting a benign role for the variant of interest (Chien_2014, Peng_2016). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three ClinVar submissions from other clinical diagnostic laboratories (evaluation after 2014) classified the variant as likely benign (1x) and benign (2x). Based on the evidence outlined above, the variant was classified as benign.
Broad Institute Rare Disease Group, Broad Institute RCV000528796 SCV001422736 benign Glycogen storage disease, type II 2020-01-22 no assertion criteria provided curation The p.Gln429Arg variant in GAA has been reported in one Taiwanese individual with glycogen storage disease II (PMID: 25466677). This variant has also been reported in ClinVar as benign by EGL Genetic Diagnostics and Invitae, and as likely benign by GeneDx (VariantID: 284497). This variant has been identified in 1.03% (196/19070) of East Asian chromosomes, 0.03% (1/29316) of South Asian chromosomes, and 0.002% (2/119604) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD,; dbSNP rs200294882). This variant has been seen in the general population at a frequency high enough to rule out a pathogenic role. Computational prediction tools, including splice predictors, and conservation analyses suggest that this variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. This variant was found in cis with another pathogenic variant, suggesting that it may not cause disease (PMID: 25466677; Variation ID: 423925). In summary, this variant meets criteria to be classified as benign for glycogen storage disease II in an autosomal recessive manner based on its high frequency in the general population and the presence of the same amino acid in other mammals. ACMG/AMP Criteria applied: BA1, BP2, BP4 (Richards 2015).

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