Variant: NM_000330.4(RS1):c.304C>T (p.Arg102Trp)

CA226667

9887 (ClinVar)

Gene: RS1

Condition: X-linked retinoschisis

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

UUID: 85b41b42-e14f-46af-ae75-6c3e6bb93d67

Approved on: 2025-05-19

Published on: 2025-05-20

HGVS expressions

NM_000330.4:c.304C>T
NM_000330.4(RS1):c.304C>T (p.Arg102Trp)
NC_000023.11:g.18647213G>A
CM000685.2:g.18647213G>A
NC_000023.10:g.18665333G>A
CM000685.1:g.18665333G>A
NC_000023.9:g.18575254G>A
NG_008475.1:g.226609G>A
NG_008659.3:g.35236C>T
ENST00000379984.4:c.304C>T
ENST00000379984.3:c.304C>T
ENST00000379989.6:c.2797+1123G>A
ENST00000379996.7:c.2797+1123G>A
ENST00000476595.1:n.795C>T
NM_000330.3:c.304C>T
NM_001037343.1:c.2797+1123G>A
NM_003159.2:c.2797+1123G>A
NM_001037343.2:c.2797+1123G>A
NM_003159.3:c.2797+1123G>A

Pathogenic

• Met criteria codes: PS4 PP3_Strong PP4 PP1_Strong

• Not Met criteria codes: PM2 BS1

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.304C>T variant is a missense variant encoding the substitution of Arginine with Tryptophan at amino acid 102. This variant is present in gnomAD v.4.1.0 at a frequency of 0.000008256 among hemizygous individuals, with 3 variant alleles / 363368 total hemizygous alleles, which is between the ClinGen X-linked IRD VCEP PM2_Supporting and BS1 thresholds of <0.000002 and >0.00002 and fails to meet these criteria. The computational predictor REVEL gives a score of 0.958, which is above the ClinGen X-linked IRD VCEP threshold of >0.932 and predicts a damaging effect on RS1 function (PP3_strong). The computational splicing predictor SpliceAI gives a delta score of 0.01 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. The variant has been reported to segregate with retinal dystrophy through 3 meioses in a family including two affected brothers and 5 other affected members (PP1_strong; PMID: 36695495, 9326935, 16901436, 24634885). 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 (5 points, PMID: 24634885, PP4). This variant has been reported in at least 5 apparently unrelated probands meeting one of the PS4 requirements of a male diagnosed with X-linked retinoschisis (PMIDs: 33124204, 9326935, 22245991, 36695495, 28348004, 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: PP3_strong, PP1_strong, PS4, and PP4 (date of approval 01/24/2025).

Met criteria codes

• PS4: This variant has been reported in at least 5 apparently unrelated probands meeting one of the PS4 requirements of a male diagnosed with XLRS (PMIDs: 33124204, 9326935, 22245991, 36695495, 28348004, 35456481, PS4).
• PP3_Strong: The computational predictor REVEL gives a score of 0.958, which is above the ClinGen X-linked IRD VCEP threshold of >0.932 and predicts a damaging effect on RS1 function (PP3_strong). The computational splicing predictor SpliceAI gives a delta score of 0.01 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.
• PP4: At least one proband harboring this variant exhibits a phenotype including appearance of schisis and reduced visual acuity before age 13 years, and was diagnosed with XLRS, which together are specific for X-linked retinoschisis (5 points, PMID: 24634885, PP4).
• PP1_Strong: The variant has been reported to segregate with retinal dystrophy through 3 meiosis in a family- One family included two affected brothers and the other 5 affected members. (PP1; PMID: 36695495, 9326935, 16901436, 24634885).

Not Met criteria codes

• PM2: This variant is present in gnomAD v.4.1.0 at a frequency of 0.000008256 among hemizygous individuals, with 3 variant alleles / 363368 total hemizygous alleles, which is between the ClinGen X-linked IRD VCEP PM2_Supporting and BS1 threshold of 0.000002 to 0.00002 and fails to meet these criteria.
• BS1: This variant is present in gnomAD v.4.1.0 at a frequency of 0.000008256 among hemizygous individuals, with 3 variant alleles / 363368 total hemizygous alleles, which is between the ClinGen X-linked IRD VCEP PM2_Supporting and BS1 threshold of 0.000002 to 0.00002 and fails to meet these criteria.