The NM_000330.4(RS1):c.598C>T (p.Arg200Cys) variant is a missense variant encoding the substitution of Arginine and Cystine at amino acid 200. This variant is absent from hemizygous individuals in gnomAD v4.1.0 (PM2_Supporting). The computational predictor REVEL gives a score of 0.944, which is above the ClinGen X-linked IRD VCEP threshold of >0.932 and predicts a damaging effect on RS1 function (PP3_strong). The computational splicing predictor SpliceAI gives a delta score of 0.00 for all predictive splice changes, which is below the ClinGen X-linked IRD VCEP threshold of >0.2 and does not predict that the variant disrupts RS1 splicing. COS-7 cells exogenously expressing the variant exhibit loss of RS1 secretion into the medium relative to the wild-type control (PMID: 20809529, PS3_Supporting). This variant has been reported in at least ≥9 apparently unrelated probands meeting the PS4 requirement of a male diagnosed with XLRS (PMIDs: 10450864, 10636421, 15937075, 17615541, 17631851, 18541843, 29739629, 35456481, 36377647, PS4_Very strong). The variant has been reported to segregate with retinal dystrophy through >3 meioses in more than two families (PP1_Strong; PMIDs: 17615541, 10636421, 17631851). In summary, this variant is classified as pathogenic for X-linked retinoschisis based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RS1 Version 1.0.0: PM2_Supporting, PP3_Strong, PS3_Supporting, PS4_Very_Strong, and PP1_Strong.