ClinVar Miner

Submissions for variant NM_000152.5(GAA):c.257C>G (p.Pro86Arg) (rs2229222)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Clinical Services Laboratory,Illumina RCV000399666 SCV000407256 uncertain significance Glycogen storage disease, type II 2018-01-12 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000595797 SCV000702184 benign not specified 2016-10-05 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000595797 SCV000917389 likely benign not specified 2018-02-23 criteria provided, single submitter clinical testing Variant summary: GAA c.257C>G (p.Pro86Arg) involves the alteration of a conserved nucleotide that results in a non-conservative amino acid change located in the P-type trefoil domain (IPR000519) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 1.78 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), strongly suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. To our knowledge, no occurrence of c.257C>G in individuals affected with Glycogen Storage Disease, Type 2 (Pompe Disease) and no experimental evidence demonstrating its impact on protein function have been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign.
Invitae RCV000399666 SCV001013875 likely benign Glycogen storage disease, type II 2020-12-04 criteria provided, single submitter clinical testing
Nilou-Genome Lab RCV000399666 SCV001653429 likely benign Glycogen storage disease, type II 2021-05-18 criteria provided, single submitter clinical testing
Mayo Clinic Laboratories, Mayo Clinic RCV001508997 SCV001715470 uncertain significance not provided 2019-12-27 criteria provided, single submitter clinical testing
Broad Institute Rare Disease Group, Broad Institute RCV000399666 SCV001422663 likely benign Glycogen storage disease, type II 2020-01-22 no assertion criteria provided curation The p.Pro86Arg variant in GAA has not been previously reported in individuals with Glycogen Storage Disease II, but has been reported as a VUS by Illumina, a likely benign variant by Integrated Genetics, and a benign variant by EGL Genetic Diagnostics in ClinVar (Variation ID: 325776). This variant has been identified in 0.749% (149/19884) of East Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs2229222). This variant has been seen in the general population at a greater frequency than expected for Glycogen Storage Disease II and is consistent with a benign role. Computational prediction tools and conservation analyses suggest that this variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely benign. ACMG/AMP Criteria applied: BS1, BP4 (Richards 2015).
Natera, Inc. RCV000399666 SCV001463469 likely benign Glycogen storage disease, type II 2020-01-12 no assertion criteria provided clinical testing

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