ClinVar Genomic variation as it relates to human health

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg197 amino acid residue in RS1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9618178, 10636421, 25799783, 30652005). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects RS1 function (PMID: 29851975). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt RS1 protein function. ClinVar contains an entry for this variant (Variation ID: 98997). This missense change has been observed in individuals with X-linked retinoschisis (PMID: 9618178, 27246168, 29851975, 30652005). This variant is present in population databases (rs281865355, gnomAD 0.006%). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 197 of the RS1 protein (p.Arg197His).

This variant is interpreted as a Likely Pathogenic, for Retinoschisis juvenile X-linked 1, in X-linked Recessive manner. The following ACMG Tag(s) were applied: PM2 => Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. PS4-Moderate => Observed in multiple unrelated patients. (PMID:17631851,29081674,27246168,28450823,19390641). PM5 => Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before. PP3 => Multiple lines of computational evidence support a deleterious effect on the gene or gene product. PP1 => Cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease (PMID:17631851).

The R197H missense variant in the RS1 gene has been reported previously in multiple unrelated individuals with X-linked retinoschisis (The Retinoschisis Consortium, 1998; Sadaka and Sisk, 2016; Sergeev et al., 2013). This variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The R197H variant is a conservative amino acid substitution, which should be unlikely to impact secondary protein structure as these residues share similar properties. However, this substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. In addition, missense variants in the same codon (R197S, R197C, R197P) and nearby residues (I194N, I195V, I199T, R200S, R200C, R200H) have been reported in the Human Gene Mutation Database in association with retinoschisis (Stenson et al., 2014; Inoue et al., 2000), supporting the functional importance of this region of the protein. We interpret R197H as a pathogenic variant.