Evidence Repository
The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]
  • Gene label mismatch: RS1 vs undefined
  • Gene obtained from curated document aligns with the Allele Registry but not with ClinVar data
  • No CSPEC computed assertion could be determined for this classification!

Variant: NM_000330.4(RS1):c.498C>A (p.Tyr166Ter)

CA16042049

370754 (ClinVar)

Gene: RS1
Condition: X-linked retinoschisis
Inheritance Mode: X-linked inheritance (recessive (HP:0001419))
Link to MONDO
UUID: 0c29e9be-dd37-4078-a7d8-4dd853294ac9
Approved on: 2025-05-19
Published on: 2025-05-20

HGVS expressions

NM_000330.4:c.498C>A
NM_000330.4(RS1):c.498C>A (p.Tyr166Ter)
NC_000023.11:g.18644454G>T
CM000685.2:g.18644454G>T
NC_000023.10:g.18662574G>T
CM000685.1:g.18662574G>T
NC_000023.9:g.18572495G>T
NG_008475.1:g.223850G>T
NG_008659.3:g.37995C>A
ENST00000379984.4:c.498C>A
ENST00000379984.3:c.498C>A
ENST00000379989.6:c.2714-1553G>T
ENST00000379996.7:c.2714-1553G>T
ENST00000476595.1:n.989C>A
NM_000330.3:c.498C>A
NM_001037343.1:c.2714-1553G>T
NM_003159.2:c.2714-1553G>T
NM_001037343.2:c.2714-1553G>T
NM_003159.3:c.2714-1553G>T
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Pathogenic

Met criteria codes 3
PM2_Supporting PVS1 PS4_Supporting

Evidence Links 0

Expert Panel

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

Criteria Specification Approval History
Criteria Specifications for this VCEP
Evidence submitted by expert panel
X-linked Inherited Retinal Disease VCEP
The NM_000330.4(RS1):c.498C>A variant is a nonsense variant in amino acid 166, which results in a premature stop codon and causes a truncated protein. This variant is absent from hemizygous individuals in gnomAD v4.1.0 (PM2_Supporting). This is a nonsense variant that introduces a premature stop codon between amino acids 1-223 that is predicted to either trigger nonsense-mediated decay or to disrupt a critical C-terminal region required for proper multimerization of RS1 (PVS1, PMID: 19849666). This variant has been reported in at least 2 apparently unrelated probands meeting the PS4 requirement of a male diagnosed with X-linked retinoschisis (PMIDs: 30025115, 32860923, 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, PVS1, and PS4_supporting (date of approval 01/24/2025).
Met criteria codes
PM2_Supporting
This variant is absent from hemizygous individuals in gnomAD v4.1.0 (PM2_Supporting).
PVS1
This is a nonsense variant that introduces a premature stop codon between amino acids 1-223 that is predicted to either trigger nonsense-mediated decay or to disrupt a critical C-terminal region required for proper multimerization of RS1 (PVS1, PMID: 19849666).
PS4_Supporting
This variant has been reported in at least 2 apparently unrelated probands meeting the PS4 requirement of a male diagnosed with XLRS (PMIDs: 30025115, 32860923, PS4_Supporting).
Curation History
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