The NM_000330.4(RS1):c.575C>T (p.Pro192Leu) variant is a missense variant encoding the substitution of Proline and Leucine at amino acid 192. This variant is absent from hemizygous individuals in gnomAD v4.1.0 (PM2_Supporting). The computational predictor REVEL gives a score of 0.963, 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 0.02 for donor gain, which is below the ClinGen X-linked IRD VCEP threshold of >0.2 and does not predict that the variant disrupts RS1 splicing. At least one proband harboring this variant exhibits a phenotype including the appearance of schisis and reduced visual acuity before age 13 years, and showing retinal detachment, which together are highly specific for X-linked retinoschisis (PMID: 32300273, PP4_Moderate). This variant has been reported in at least 5 apparently unrelated probands meeting one of the PS4 requirements of a male diagnosed with XLRS (PMIDs: 19093009, 19324861, 28348004, 33124204, 36460718, PS4). 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, PP4_Moderate, and PS4.