ClinVar

Description

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.