rs369484186

Description

The I1002F variant in the TRPM1 gene has been reported previously in an individual with congenital stationary night blindness who was also heterozygous for another missense variant, however familial segregation information was not included (Li et al., 2009). The I1002F variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The I1002F variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret I1002F as a variant of uncertain significance.

This sequence change replaces isoleucine with phenylalanine at codon 1002 of the TRPM1 protein (p.Ile1002Phe). The isoleucine residue is highly conserved and there is a small physicochemical difference between isoleucine and phenylalanine. This variant is present in population databases (rs369484186, ExAC 0.004%). This missense change has been observed in individual(s) with congenital stationary night blindness (PMID: 19878917, 28041643, 29074561). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 290045). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.