ClinVar

Description

A novel R154M (c.461 G>T) variant that is likely pathogenic was identified in the MPV17 gene. It has not been published as a pathogenic variant, nor has it been reported as a benign polymorphism to our knowledge. The R154M missense change is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is highly conserved across species and in silico analysis predicts this variant is probably damaging to the protein structure/function. A missense variant in a nearby residue (A162D) has been reported in the Human Gene Mutation Database in association with mitochondrial DNA depletion syndrome (Stenson et al., 2014), supporting the functional importance of this region of the protein. Additionally, several in-silico splice prediction models predict that the c.461 G>T nucleotide substitution, responsible for R154M, damages the natural splice donor site for exon 7 which may lead to abnormal gene splicing. However, in the absence of RNA/functional studies, the actual effect of the c.461 G>T sequence change in this individual is unknown. Therefore, R154M (c.461 G>T) is a strong candidate for a pathogenic variant, however the possibility that it is a benign variant cannot be excluded.