The NM_000330.4(RS1):c.214G>C (p.Glu72Gln) variant is a missense variant encoding the substitution of Glutamic acid and Glutamine at amino acid 72. This variant is absent from hemizygous individuals in gnomAD v4.1.0 (PM2_Supporting). The computational predictor REVEL gives a score of 0.931, 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 0.05 for acceptor gain, which is below the ClinGen X-linked IRD VCEP threshold of >0.2 and does not predict that the variant disrupts RS1 splicing. This variant p.Glu72, of the RS1 gene, is a missense substitution affecting an established residue involved in cross-linking the adjacent RS1 subunit defined by the ClinGen X-linked IRD VCEP (PMID: 27114531, PM1). 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: 19390641, PP4). The variant has been reported to segregate with retinal dystrophy through two brothers (PP1; PMID: 11295123). This variant has been reported in at least 5 apparently unrelated probands meeting the PS4 requirement of a male diagnosed with XLRS (PMIDs: 11295123, 28348004, 36460718, 39462066, 35456481, 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_Moderate, PM1, PP4, PP1, and PS4.