ClinVar

Description

The R389H pathogenic variant in the TGM1 gene has been reported previously either in combination with another TGM1 variant or in the homozygous state in individuals with autosomal recessive congenital ichthyosis (Akiyama et al., 2001; Esposito et al., 2014). This variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). The R389H variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. However, this substitution occurs at a position in the core domain (Akiyama et al., 2001) that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. A different missense variant in the same codon (R389P) has also been reported in association with congenital ichthyosis (Schevchenko et al., 2000; Oji et al., 2006), supporting the functional importance of this region of the protein. We interpret R389H as a pathogenic variant.