Evidence Repository - Clinical Genome Resources

The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]

Variant: NM_003159.3:c.2714-1476G>T

CA412371862

Gene: CDKL5 (HGNC:6792)

Condition: X-linked retinoschisis (MONDO:0010725)

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

UUID: 87406abb-43dc-40c9-8538-4db5f8593da9

Approved on: 2025-09-22

Published on: 2025-09-22

HGVS expressions

NM_003159.3:c.2714-1476G>T

NC_000023.11:g.18644531G>T

CM000685.2:g.18644531G>T

NC_000023.10:g.18662651G>T

CM000685.1:g.18662651G>T

NC_000023.9:g.18572572G>T

NG_008475.1:g.223927G>T

NG_008659.3:g.37918C>A

ENST00000379984.4:c.421C>A

ENST00000379984.3:c.421C>A

ENST00000379989.6:c.2714-1476G>T

ENST00000379996.7:c.2714-1476G>T

ENST00000476595.1:n.912C>A

NM_000330.3:c.421C>A

NM_001037343.1:c.2714-1476G>T

NM_003159.2:c.2714-1476G>T

NM_000330.4:c.421C>A

NM_001037343.2:c.2714-1476G>T

Likely Pathogenic

PM5 PS4_Supporting PS3_Supporting PM2_Supporting PP4 PP3

Evidence Links 1

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

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

X-linked Inherited Retinal Disease VCEP

NM_000330.4(RS1):c.421C>A (p.Arg141Ser) is a missense variant encoding the substitution of arginine with serine at amino acid 141. Another missense variant in the same codon, NM_000330.4(RS1):c.422G>A (p.Arg141His), (PMID: 29851975, PMID: 34645606, PMID: 30450322, PMID: 29739629, PMID: 35984651, PMID: 30652005, PMID: 19093009, PMID: 30630865, PMID: 30040949, PMID: 17525175, PMID: 30630865, PMID: 30040949) 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. The present variant has a higher Grantham’s distance (110) than the comparison variant (29), and SpliceAI has been used to confirm that neither variant has a predicted impact on RS1 splicing (PM5). This variant is absent from hemizygous individuals in gnomAD v4.1.0 (PM2_Supporting). At least one proband harboring this variant exhibits a phenotype of the appearance of schisis and reduced visual acuity before age 13 years, which together are specific for X-linked retinoschisis (PMID: 29851975, PP4). This variant has been reported in at least 1 proband meeting the PS4 requirement of a male diagnosed with X-linked retinoschisis, as well as a second apparently unrelated proband previously used for the PP4 code (PMID: 34645606, PS4_Supporting). The computational predictor REVEL gives a score of 0.765, which is within the ClinGen X-linked IRD VCEP range between 0.772 to 0.644 and predicts a damaging effect on RS1 function (PP3). The computational splicing predictor SpliceAI gives a delta score of 0.02 for acceptor loss, which is below the ClinGen X linked IRD VCEP threshold of ≥0.2 and does not predict that the variant disrupts RS1 splicing. Carbohydrate-agarose affinity chromatography assays of wild-type and variant RS1 secreted from Weri-Rb1 cells showed reduced binding to galactose-agarose by RS1 harboring the variant relative to the wild-type control (PS3_Supporting, PMID: 18690710). In summary, this variant is classified as likely 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, PS3_Supporting, PP4, PS4_Supporting, and PM5.

PM5

Another missense variant in the same codon, [c.422G>A, p. Arg141His], (PMID: 19093009) 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. The present variant has a higher Grantham’s distance than the comparison variant, and SpliceAI has been used to confirm that neither variant has a predicted impact on RS1 splicing (PM5).

PS4_Supporting

This variant has been reported in at least 1 proband meeting the PS4 requirement of a male diagnosed with XLRS, as well as a second apparently unrelated proband previously used for the PP4 code (PMIDs: PMID: 34645606, PS4_Supporting).

PS3_Supporting

Carbohydrate-agarose affinity chromatography assays of wild-type and variant RS1 secreted from Weri-Rb1 cells showed reduced binding to galactose-agarose by RS1 harboring the variant relative to the wild-type control (PS3_Supporting, PMID: 18690710).

Dyka et al. showed reduced binding of the RS1 to galactose-agarose than WT. PubMed:18690710

PM2_Supporting

This variant is absent from hemizygous individuals in gnomAD v4.1.0 (PM2_Supporting).

PP4

At least one proband harboring this variant exhibits a phenotype of the appearance of schisis and reduced visual acuity before age 13 years, which together are specific for X-linked retinoschisis (PMID: 29851975, PP4).

PP3

The computational predictor REVEL gives a score of [0.765], which is within the ClinGen X-linked IRD VCEP range between 0.772 to 0.644 and predicts a damaging effect on RS1 function (PP3). The computational splicing predictor SpliceAI gives a delta score of [0.02] for [ acceptor loss ], which is below the ClinGen X linked IRD VCEP threshold of ≥0.2 and does not predict that the variant disrupts RS1 splicing.

Curation History

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. If you have questions about the information contained on this website, please see a health care professional.