ClinVar

Description

A variant of unknown significance has been identified in the GAMT gene. The M42V variant has not been published as a pathogenic variant, nor has it been reported as a benign polymorphism to our knowledge. It was not observed in approximately 6,300 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations; however the 1000 Genomes Project reports that M42V was observed in 2/172 (1.2%) alleles from individuals of Bangladeshi background. This substitution alters a conserved position, and missense mutations in nearby residues (W45R, M50L, H51P) have been reported in the Human Gene Mutation Database in association with GAMT deficiency (Stenson et al., 2014), supporting the functional importance of this region of the protein. Additionally, in silico analysis predicts this variant is probably damaging to the protein structure/function. However, the M42V variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.