Variant: NM_000330.4:c.176G>C

CA412376053

Gene: RS1

Condition: X-linked retinoschisis

Inheritance Mode: X-linked inheritance (recessive (HP:0001419))

UUID: 14c77a7f-6f44-418e-a6c1-ba24d2143e54

Approved on: 2025-05-19

Published on: 2025-05-20

HGVS expressions

NM_000330.4:c.176G>C
NC_000023.11:g.18656661C>G
CM000685.2:g.18656661C>G
NC_000023.10:g.18674781C>G
CM000685.1:g.18674781C>G
NC_000023.9:g.18584702C>G
NG_008659.3:g.25788G>C
ENST00000379984.4:c.176G>C
ENST00000379984.3:c.176G>C
NM_000330.3:c.176G>C

Pathogenic

• Met criteria codes: PP4 PS1 PS4_Supporting PM2_Supporting PP3_Moderate PS3_Supporting

• Not Met criteria codes: PM1

Expert Panel

X-linked Inherited Retinal Disease VCEP

Criteria Specification Information

Criteria Specification: ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RS1 Version 1.0.0

Evidence submitted by expert panel

X-linked Inherited Retinal Disease VCEP

The NM_000330.4(RS1):c.176G>C variant is a missense variant encoding the substitution of Cysteine with Serine at position 59 and results in the disruption of the disulfide bridge between amino acids Cys59 and Cys223. This variant is absent from hemizygous individuals in gnomAD v4.1.0 (PM2_Supporting). The computational predictor REVEL gives a score of 0.878, which is within the ClinGen X-linked IRD VCEP range between 0.931 to 0.773 and predicts a damaging effect on RS1 function (PP3_moderate). 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. A missense variant encoding the same amino acid substitution, NM_000330.4(RS1):c.175T>A (p.Cys59Ser), (PMIDs: 35982512, 9618178, 17987333, 10450864) has been classified as pathogenic for X-linked retinoschisis by the ClinGen X-linked IRD VCEP, while no benign missense variants have been identified in this codon. SpliceAI has been used to confirm that neither variant has a predicted impact on RS1 splicing (PS1). This variant, p.Cys59Ser, of the RS1 gene, is defined as a critical amino acid residue involved in disulfide bridge formation by the ClinGen X-linked IRD VCEP (PMIDs: 26812435). The PM1_strong code is ineligible to be combined with PP3 at any strength, therefore, the PM1 code was not met. HEK293 or COS7 cells exogenously expressing the variant exhibit loss of RS1 secretion into the medium relative to the wild-type control. Moreover, exogenously expressed RS1 harboring the variant exhibits aberrant immunofluorescent localization of RS1 to the ER/Golgi relative to the wild-type control. Exogenously expressed RS1 harboring the variant was subjected to co-assembly and successful secretion and exhibits defective oligomerization indicating no formation of octomers (PMID: 12746437, 17525175, 19849666, 22245536, 26812435, PS3_supporting). 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: 23288992, PP4). This variant has been reported in at least another 2 apparently unrelated probands carrying this variant and diagnosed with X-linked retinoschisis (PMIDs: 35456481, 34645606, PS4_supporting). 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, PS1, PS3_supporting, PS4_supporting, and PP4 (date of approval 01/24/2025).

Met criteria codes

• PP4: 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: 23288992, PP4).
• PS1: A missense variant encoding the same amino acid substitution, NM_000330.4(RS1):c.175T>A (p.Cys59Ser), (PMIDs: 35982512, 9618178, 17987333, 10450864) has been classified as pathogenic for X-linked retinoschisis by the ClinGen X-linked IRD VCEP, while no benign missense variants have been identified in this codon. SpliceAI has been used to confirm that neither variant has a predicted impact on RS1 splicing (PS1).
• PS4_Supporting: This variant has been reported in at least another 2 apparently unrelated probands carrying this variant and diagnosed with XLRS (PMIDs: 35456481, 34645606, PS4_supporting).
• PM2_Supporting: This variant is absent from hemizygous individuals in gnomAD v4.1.0 (PM2_Supporting).
• PP3_Moderate: The computational predictor REVEL gives a score of 0.878, which is within the ClinGen X-linked IRD VCEP range between 0.931 to 0.773 and predicts a damaging effect on RS1 function (PP3_moderate). 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.
• PS3_Supporting: HEK293/ COS7 cells exogenously expressing the variant exhibit loss of RS1 secretion into the medium relative to the wild-type control. Moreover, Exogenously expressed RS1 harboring the variant exhibits aberrant immunofluorescent localization of RS1 to the ER/Golgi relative to the wild-type control. Exogenously expressed RS1 harboring the variant was subjected to co-assembly and successful secretion and exhibits defective oligomerization indicating no formation of octomers (PMID: 12746437, 17525175, 19849666, 22245536, 26812435, PS3_supporting).

Not Met criteria codes

• PM1: This variant, p.Cys59Ser, of the RS1 gene, is defined as a critical amino acid residue involved in disulfide bridge formation by the ClinGen X-linked IRD VCEP (PMIDs: 26812435). The PM1_strong code is ineligible to be combined with PP3 at any strength, therefore, the PM1 code was not met.