Description
The c.1071 A>C (K357N) variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). K357N is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position within the NACHT domain that is conserved in mammals; this domain is a major locus for CAPS-associated pathogenic variants (Masters et al., 2009). In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. However, a distinct nucleotide change leading to the same missense variant, c.1071 A>T (K357N), has been reported in in the Human Gene Mutation Database in association with NOMID/CINCA syndrome (Stenson et al., 2014). Functional studies have shown that the c.1071 A>T variant causes increased rates of THP-1 cell death and ASC-dependent NF-kB activation (Tanaka et al., 2011). Additionally, other missense variants in the same codon (K357T) and in nearby residues (V353L/M, A354T/V, L355P, E356D, H360R, L361V) have been reported in the Human Gene Mutation Database in association with NLRP3-related disorders (Stenson et al., 2014), supporting the functional importance of this region of the protein. In summary, we consider the c.1071 A>C (K357N) variant to be pathogenic.
| # | Sample | Method | Observation |
|---|
| Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences |
|---|
| 1 | germline | yes | not provided | not provided | not provided | | not provided | not provided | not provided | not provided |
