Total submissions: 1
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000481361 | SCV000570199 | likely pathogenic | not provided | 2017-11-16 | criteria provided, single submitter | clinical testing | The F435L variant in the TGM1 has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. This variant is not observed in large population cohorts (Lek et al., 2016). The F435L variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Nevertheless, in-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect, as the F435 codon is important for the positioning of the catalytic H436 residue based on TGase-1 protein modeling (Herman et al., 2009). Additionally, other missense variants at the same codon (F435V) and in nearby residues (D430V, H436D, and V437G) have been reported in the Human Gene Mutation Database in association with autosomal recessive congenital ichthyosis (Stenson et al., 2014), supporting the functional importance of this region of the protein. Therefore, we interpret F435L as a likely pathogenic variant. |