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.2714-1477C>A

CA412371854

Gene: CDKL5 (HGNC:6792)

Condition: X-linked retinoschisis (MONDO:0010725)

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

UUID: 22316273-d684-4038-957c-548403c21bce

Approved on: 2025-09-22

Published on: 2025-09-22

HGVS expressions

NM_003159.3:c.2714-1477C>A

NC_000023.11:g.18644530C>A

CM000685.2:g.18644530C>A

NC_000023.10:g.18662650C>A

CM000685.1:g.18662650C>A

NC_000023.9:g.18572571C>A

NG_008475.1:g.223926C>A

NG_008659.3:g.37919G>T

ENST00000379984.4:c.422G>T

ENST00000379984.3:c.422G>T

ENST00000379989.6:c.2714-1477C>A

ENST00000379996.7:c.2714-1477C>A

ENST00000476595.1:n.913G>T

NM_000330.3:c.422G>T

NM_001037343.1:c.2714-1477C>A

NM_003159.2:c.2714-1477C>A

NM_000330.4:c.422G>T

NM_001037343.2:c.2714-1477C>A

Likely Pathogenic

PP3_Strong PS4_Moderate PM5 PM2_Supporting

Evidence Links 0

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.422G>T (p.Arg141Leu) is a missense variant encoding the substitution of arginine with leucine 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 (102) 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). This variant has been reported in at least 3 apparently unrelated probands meeting one of the PS4 requirements of a male diagnosed with X-linked retinoschisis (PMID: 34645606, PMID: 28771251, PMID: 34822951, PMID: 38219857, PS4_Moderate). The computational predictor REVEL gives a score of 0.939, 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 0.02 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. 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_Strong, PM5, and PS4_Moderate.

PP3_Strong

The computational predictor REVEL gives a score of 0.939, 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 0.02 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.

PS4_Moderate

This variant has been reported in at least 3 apparently unrelated probands meeting one of the PS4 requirements of a male diagnosed with X-linked retinoschisis (PMID: 34645606, PMID: 28771251, PMID: 34822951, PMID: 38219857, PS4_Moderate).

PM5

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 (102) than the comparison variant (29), and SpliceAI has been used to confirm that neither variant has a predicted impact on RS1 splicing (PM5).

PM2_Supporting

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

Curation History

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