ClinVar

Description

Variant summary: NPPA c.272A>G (p.Gln91Arg) 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 0.00017 in 249000 control chromosomes, predominantly at a frequency of 0.0021 within the East Asian subpopulation in the gnomAD database. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 210-folds higher than the estimated maximal expected allele frequency for a pathogenic variant in NPPA causing Arrhythmia phenotype (1e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. c.272A>G has been reported in the literature in individual affected with Arrhythmia, although authors believe the variant to be a polymorphism (Ren_2011). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. A ClinVar submission (evaluation after 2014) cites the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as benign.