ClinVar Genomic variation as it relates to human health

Variant summary: NPPA c.190A>C (p.Ser64Arg) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.002 in 263016 control chromosomes, predominantly at a frequency of 0.0029 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 92.8 fold of the estimated maximal expected allele frequency for a pathogenic variant in NPPA causing Atrial Fibrillation phenotype (3.1e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.190A>C has been reported in the literature in multiple individuals affected with Atrial Fibrillation and Arrythmia, but also in healthy controls (example: Abraham_2010, Ritchie_2012, Disertori_2012, Disertori_2016, Hertz_2014, Hertz_2016, Guelly_2020). Co-occurrences with other pathogenic variants have been reported (SCN5A c.361C>T / p.Arg121Trp, Hertz_2014; KCNH2 c.2587C>T / p.Arg863X, internal sample), providing supporting evidence for a benign role. At least one publication reports experimental evidence evaluating an impact on protein function, reporting an increased potassium current associated with this variant (Abraham_2010). However, a case-control study reported that the variant was relatively common among non-AF controls, which suggested that it may not be causative i.e. the monogenic cause of AF, though it might be associated with very low penetrance or contribute in some as yet undefined fashion to AF susceptibility (Weeke_2015). Two ClinVar submitters have assessed this variant since 2014: one classified the variant as likely benign and the other as benign. Based on the evidence outlined above, the variant was classified as benign.

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).