Letter regarding “SCN9A variant in a family of mixed breed dogs with congenital insensitivity to pain”—Navigating the pathogenicity of candidate gene mutations: Spotlight on paralog Nav genes

In their study, the authors conducted whole-genome sequencing analysis of a dog with congenital insensitivity to pain and identified the pathogenic variant c.C2761T (p.R921C) in SCN9A, which encodes the alpha subunit of voltage-gated neuronal sodium channel Nav1.7 that is mainly expressed in nociceptive neurons. 2 Furthermore, the authors speculated that the Nav1.7-R921C variant is disease-causing based on five perspectives: evolutionarily conserved amino acid sequences, comparisons with a large amount of genetic data of healthy controls, in-silico functional prediction, functional impacts of arginine substitution, and reference to human clinic data. [...]the authors compared whole genome sequence data of the affected dog with those of 926 healthy control dogs, and found that the SCN9A-C2761T allele was absent in controls. [...]the authors used three in-silico prediction programs, and determined Nav1.7-R921C as deleterious. [...]the ACMG-AMP guideline recognizes that in-silico prediction is a weak evidence annotation tool to assign pathogenicity. 3 Fourth, the authors speculated that Nav1.7-R921C was a functionally altered variant by explaining the substitution of a positively charged arginine residue with cysteine.