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_025114.4(CEP290):c.21G>T (p.Trp7Cys)

CA227962

1335 (ClinVar)

Gene: CEP290 (HGNC:80184)

Condition: CEP290-related ciliopathy (MONDO:0100451)

Inheritance Mode: Autosomal recessive inheritance

UUID: 9dbcefbe-11bc-4af8-9f23-1a7b31da7f12

Approved on: 2026-07-20

Published on: 2026-07-20

HGVS expressions

NM_025114.4(CEP290):c.21G>T (p.Trp7Cys)

NM_025114.4:c.21G>T

NC_000012.12:g.88141287C>A

CM000674.2:g.88141287C>A

NC_000012.11:g.88535064C>A

CM000674.1:g.88535064C>A

NC_000012.10:g.87059195C>A

NG_008417.1:g.5930G>T

NG_021187.1:g.3992C>A

NG_008417.2:g.5930G>T

ENST00000309041.12:c.21G>T

ENST00000397838.8:c.21G>T

ENST00000547926.7:c.21G>T

ENST00000550962.6:c.21G>T

ENST00000552770.3:c.21G>T

ENST00000552810.6:c.21G>T

ENST00000671822.2:n.248G>T

ENST00000672414.2:c.21G>T

ENST00000673058.2:c.21G>T

ENST00000674971.1:c.21G>T

ENST00000675230.1:c.21G>T

ENST00000675361.1:c.21G>T

ENST00000675408.1:c.21G>T

ENST00000675476.1:c.21G>T

ENST00000675559.1:c.21G>T

ENST00000675628.1:n.248G>T

ENST00000675794.1:c.21G>T

ENST00000675833.1:c.21G>T

ENST00000676074.1:c.21G>T

ENST00000676331.1:n.248G>T

ENST00000676351.1:c.21G>T

ENST00000676418.1:c.21G>T

ENST00000676448.1:c.21G>T

ENST00000309041.11:c.21G>T

ENST00000397838.7:c.21G>T

ENST00000550962.5:c.21G>T

ENST00000552810.5:c.21G>T

NM_025114.3:c.21G>T

Likely Pathogenic

PM3_Strong PP4 PP3 PM2_Supporting

Evidence Links 0

Expert Panel

Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP

Criteria Specification Information

Criteria Specification: ClinGen Leber Congenital Amaurosis/early onset Retinal Dystrophy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for CEP290 Version 1.0

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP

NM_025114.4(CEP290):c.21G>T (p.Trp7Cys) is a missense variant that replaces tryptophan with cysteine at amino acid 7. This variant is present in gnomAD v4.1.1 at a total allele frequency of 0.0000006208, with 1 allele / 1,610,852 total alleles, which is lower than the ClinGen LCA/eoRD VCEP PM2_Supporting threshold of <0.0006 (PM2_Supporting). This variant has been reported in at least 2 probands with early-onset severe retinal dystrophy who were homozygous for the variant (PMID: 20683928, PMID: 16682970, PMID: 35764379, PMID: 17705300). The variant has also been reported in at least 2 probands who were compound heterozygous with either the NM_025114.4(CEP290):c.5324dup (p.Asn1775LysfsTer7) variant confirmed in trans (1 pt, PMID: 27422788) or the NM_025114.4(CEP290):c.4966_4967del (p.Glu1656AsnfsTer3) variant suspected in trans (0.5 pts, PMID: 21153841), which were previously classified pathogenic by the ClinGen LCA/eoRD VCEP (2.5 total points, PM3_Strong). One proband exhibits a phenotype including diagnosis of Leber congenital amaurosis (0.5 pts), congenital or infantile onset (0.5 pts), inability to fix or follow (0.5 pts), high hypermetropia, oculodigital sign (0.5 pts), and white mottling of the peripheral pigmentation (0.5 pts), with genotyping by targeted next-generation sequencing using a panel of 195 known retinal disease genes with no alternative causes identified (2 pts), which together are specific for CEP290-related ciliopathy (4 total points, PMID: 27422788, PP4). The computational predictor CADD gives a PHRED score of 25.4, which is above the ClinGen LCA/eoRD VCEP threshold of ≥25.3 and predicts a damaging effect on CEP290 protein function (PP3). The splicing impact predictor SpliceAI gives a score of 0.01 for donor loss, acceptor gain, and donor gain, which is below the ClinGen LCA/eoRD VCEP recommended threshold of ≥0.2 and does not strongly predict an impact on splicing. In summary, this variant meets the criteria to be classified as Likely Pathogenic for CEP290-related ciliopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA/eoRD VCEP: PM2_Supporting, PM3_Strong, PP4, and PP3. (LCA/eoRD VCEP Specifications for CEP290 Version 1.0.0)

PM3_Strong

This variant has been reported in at least 2 probands with early-onset severe retinal dystrophy who were homozygous for the variant (PMID: 20683928, PMID: 16682970, PMID: 35764379, PMID: 17705300). The variant has also been reported in at least 2 probands who were compound heterozygous with either the NM_025114.4(CEP290):c.5324dup (p.Asn1775LysfsTer7) variant confirmed in trans (1 pt, PMID: 27422788) or the NM_025114.4(CEP290):c.4966_4967del (p.Glu1656AsnfsTer3) variant suspected in trans (0.5 pts, PMID: 21153841), which were previously classified pathogenic by the ClinGen LCA/eoRD VCEP (2.5 total points, PM3_Strong).

PP4

The proband exhibits a phenotype including diagnosis of Leber congenital amaurosis (0.5 pts), congenital or infantile onset (0.5 pts), inability to fix or follow (0.5 pts), high hypermetropia, oculodigital sign (0.5 pts), and white mottling of the peripheral pigmentation (0.5 pts), with genotyping by targeted next-generation sequencing using a panel of 195 known retinal disease genes (2 pts), which together are specific for CEP290-related ciliopathy (4 total points, PMID: 27422788, PP4).

PP3

The computational predictor CADD gives a PHRED score of 25.4, which is above the ClinGen LCA/eoRD VCEP threshold of ≥25.3 and predicts a damaging effect on CEP290 protein function (PP3). The splicing impact predictor SpliceAI gives a score of 0.01 for donor loss, acceptor gain, and donor gain, which is below the ClinGen LCA/eoRD VCEP recommended threshold of ≥0.2 and does not strongly predict an impact on splicing.

PM2_Supporting

This variant is present in gnomAD v4.1.0 at a total allele frequency of 6.208e-7, with 1 alleles / 1610852 total alleles, which is lower than the ClinGen LCA/eoRD VCEP PM2_Supporting threshold of <0.0006 (PM2_Supporting).

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.