The NM_000330.4(RS1):c.433G>C (p.Asp145His) variant is a missense variant encoding the substitution of Aspartic acid and Histidine at amino acid 145. This variant is absent from hemizygous individuals in gnomAD v4.1.0 (PM2_Supporting). The computational predictor REVEL gives a score of 0.916, which is within the ClinGen X-linked IRD VCEP range between 0.931 and 0.773 and predicts a damaging effect on RS1 function (PP3_moderate). The computational splicing predictor SpliceAI gives a delta score of 0.04 for acceptor loss, which is below the ClinGen X-linked IRD VCEP threshold of >0.2 and does not predict that the variant disrupts RS1 splicing. Hek 293, Murine RS1h-/Y retinal and kidney cells exogenously expressing the variant exhibit loss of RS1 secretion into the medium relative to the wild-type control (PMID: 30040949, PS3_Supporting). 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: 7615541, PP4_Moderate). This variant has been reported in at least 1 proband meeting one of the PS4 requirements of a male diagnosed with XLRS, as well as a second apparently unrelated proband previously used for the PP4 code (PMIDs: 18369700, 32300273, 34624300, PS4_Supporting). 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_Moderate, PS3_Supporting, PP4_Moderate, and PS4_Supporting.