The NM_000330.4(RS1):c.574C>T (p.Pro192Ser) variant is a missense variant encoding the substitution of Proline and Serine at amino acid 192. This variant is present in gnomAD v.4.1.0 at a frequency of 0.000002506 among hemizygous individuals, with 1 variant allele / 399069 total hemizygous alleles, which is between the ClinGen X-linked IRD VCEP PM2_Supporting and BS1 threshold of 0.000002 to 0.00002 and fails to meet these criteria. The computational predictor REVEL gives a score of 0.946, 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 0.01 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. Vijayasarathy et al. tested this variant in comparison to wild-type and showed that anti-Flag antibody selectively identified epitope-tagged RS1 mutants, and this variant was not secreted (PMID: 20809529). At least one proband harboring this variant exhibits the following phenotypes, including the appearance of schisis and reduced visual acuity before age 13 years, which together are specific for X-linked retinoschisis (PMID: 17515881, PP4). This variant has been reported in at least 7 apparently unrelated probands meeting the PS4 requirement of a male diagnosed with XLRS (PMIDs: 9326935, 10636421, 17987333, 19093009, 28348004, 30551202, 30652005, 34828422, 39293640, PS4). The variant has been reported to segregate through at least 2 meioses in one family (PP1_moderate; PMID: 30551202). 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: PP3_Strong, PP4, PS4, and PP1_Moderate.