The NM_000330.4(RS1):c.52G>A (p.Ala18Thr) variant is a missense variant encoding the substitution of Alanine and Threonine at amino acid 18, located at the end of exon 1. The splicing impact predictor SpliceAI gives the variant a score of 0.31, which is above the ClinGen X-linked IRD VCEP recommended threshold of ≥0.2 and predicts a damaging impact on splicing. Functional studies confirm that the variant triggers either exon 2 or both exons 1 and 2 skipping in all transcripts (PMID: 20809529). While these in silico and experimental findings would normally be counted under the PP3 and PS3_Supporting codes, respectively, in combination, they have been counted as evidence of a loss-of-function effect (PVS1_RNA). This variant is absent from hemizygous individuals in gnomAD v4.1.0 (PM2_Supporting). 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: 20809529, PP4). The variant has been reported to segregate through at least 2 meioses in one family (PP1_moderate; PMID: 20809529). 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: PVS1_RNA, PM2_Supporting, PP4, and PP1_Moderate.