ClinVar Miner

Submissions for variant NM_000152.5(GAA):c.2647-8C>T (rs139201641)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000278787 SCV000333790 likely benign not specified 2015-08-28 criteria provided, single submitter clinical testing
GeneDx RCV000278787 SCV000528214 likely benign not specified 2017-12-11 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 RCV001000494 SCV000626588 benign Glycogen storage disease, type II 2019-12-31 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV001000494 SCV001157386 likely benign Glycogen storage disease, type II 2018-10-23 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000278787 SCV001363612 benign not specified 2019-09-09 criteria provided, single submitter clinical testing Variant summary: GAA c.2647-8C>T alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00059 in 249424 control chromosomes, predominantly at a frequency of 0.0083 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 2 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 African or African-American origin. To our knowledge, no occurrence of c.2647-8C>T in individuals affected with Glycogen Storage Disease, Type 2 (Pompe Disease) and no experimental evidence demonstrating its impact on protein function have been reported. Three submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign (1x) /likely benign (2x). Based on the evidence outlined above, the variant was classified as benign.

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