NM_000330.4(RS1):c.37C>T (p.Leu13Phe) is a missense variant encoding the substitution of leucine with phenylalanine at amino acid 13. Another missense variant in the same codon, NM_000330.4(RS1):c.38T>C (p.Leu13Pro), has been reported in association with X-linked retinoschisis (PMID: 10533068, PMID: 20809529, PMID: 30652005), but has a higher Grantham score (98) than the present variant (22), so PM5 is not met. This variant is present in gnomAD v4.1.0 at a frequency of 0.00001010 among hemizygous individuals, with 4 variant alleles / 396,100 total hemizygous alleles, which is higher than the ClinGen X-linked IRD VCEP PM2_Supporting threshold of <0.000002 but lower than the BS1 threshold of >0.00002, so neither population code is met. This variant has been reported in at least 1 proband meeting the PS4 requirement of a male diagnosed with X-linked retinoschisis (PMID: 20809529), however, PS4_Supporting requires at least 2 unrelated probands, so this criterion was not met. The computational predictor REVEL gives a score of 0.444, which is lower than the ClinGen X-linked IRD VCEP PP3 threshold of >0.664 and higher than the BP4 threshold of<0.290 and does not predict a damaging effect on RS1 function. Additionally, the splicing impact predictor SpliceAI gives a score of 0.01, which is below the ClinGen X-linked IRD VCEP recommended threshold of ≥0.2 and does not strongly predict an impact on splicing. COS7 cells exogenously expressing the variant exhibit RS1 expression and secretion into the medium at levels similar to the wild-type control (PMID: 20809529). However, the BS3_Supporting code is considered not applicable for RS1 variants due to the absence of sufficient benign control variants from established assays of RS1 function. In summary, this variant is classified as a variant of uncertain significance 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: None.