The NM_000330.4(RS1):c.647T>C variant is a missense variant encoding the substitution of Leucine with Proline at amino acid 216. This variant is absent from hemizygous individuals in gnomAD v4.1.0 (PM2_Supporting). The computational predictor REVEL gives a score of 0.969, 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. At least one proband harboring this variant exhibits a phenotype including appearance of schisis and reduced visual acuity before age 13 years, which together are specific for X-linked retinoschisis (PMID: 33460243, PP4). This variant has been reported in at least 3 apparently unrelated probands meeting the PS4 requirements of a male diagnosed with X-linked retinoschisis (PMIDs: 19324861, 19390641, 34822951, PS4_Moderate). In summary, this variant is classified as likely 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, and PS4_moderate (date of approval 01/24/2025).