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.148C>T (p.His50Tyr)

CA10581687

236469 (ClinVar)

Gene: CEP290 (HGNC:80184)

Condition: CEP290-related ciliopathy (MONDO:0100451)

Inheritance Mode: Autosomal recessive inheritance

UUID: a3fb4056-958f-4d2d-a567-0290d42c1e94

Approved on: 2026-07-20

Published on: 2026-07-20

HGVS expressions

NM_025114.4(CEP290):c.148C>T (p.His50Tyr)

NM_025114.4:c.148C>T

NC_000012.12:g.88140988G>A

CM000674.2:g.88140988G>A

NC_000012.11:g.88534765G>A

CM000674.1:g.88534765G>A

NC_000012.10:g.87058896G>A

NG_008417.1:g.6229C>T

NG_021187.1:g.3693G>A

NG_008417.2:g.6229C>T

ENST00000309041.12:c.148C>T

ENST00000397838.8:c.148C>T

ENST00000547926.7:c.148C>T

ENST00000550962.6:c.148C>T

ENST00000552770.3:c.148C>T

ENST00000552810.6:c.148C>T

ENST00000671822.2:n.375C>T

ENST00000672414.2:c.148C>T

ENST00000673058.2:c.148C>T

ENST00000674971.1:c.148C>T

ENST00000675230.1:c.148C>T

ENST00000675361.1:c.148C>T

ENST00000675408.1:c.148C>T

ENST00000675476.1:c.148C>T

ENST00000675559.1:c.148C>T

ENST00000675628.1:n.375C>T

ENST00000675794.1:c.148C>T

ENST00000675833.1:c.148C>T

ENST00000676074.1:c.148C>T

ENST00000676331.1:n.375C>T

ENST00000676351.1:c.148C>T

ENST00000676418.1:c.148C>T

ENST00000676448.1:c.148C>T

ENST00000309041.11:c.148C>T

ENST00000397838.7:c.148C>T

ENST00000547926.6:c.46C>T

ENST00000550962.5:c.148C>T

ENST00000552770.2:c.7C>T

ENST00000552810.5:c.148C>T

NM_025114.3:c.148C>T

Pathogenic

PP1_Strong PM3_Strong PM2_Supporting PP4 PP3

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.148C>T (p.His50Tyr) is a missense variant that replaces histidine with tyrosine at amino acid 50. This variant is absent from gnomAD v4.1.0 (PM2_Supporting). This variant has been reported in at least 2 unrelated probands with early-onset severe retinal dystrophy who were homozygous for the variant (1 point, PMIDs: 29398085, 28418496). This variant has also been reported in at least 1 proband with early-onset severe retinal dystrophy who was compound heterozygous with the NM_025114.4(CEP290):c.4393C>T (p.Arg1465Ter) variant confirmed in trans (1 point, PMID: 29398085), which was previously classified pathogenic by the ClinGen LCA/eoRD VCEP (2 total points, PM3_Strong). At least one proband harboring this variant exhibits a phenotype including a diagnosis of Leber congenital amaurosis (0.5 pts), symptoms present from birth (0.5 pts), severely reduced visual acuity (0.5 pts), no clear progression in first decade (0.5 pts), vision that was worse under bright light (0.5 pts), impaired night vision (0.5 pts), fundi showing widespread outer retinal atrophy with relative sparing of the macula (1 pt), and optical coherence tomography showed only a small region of preservation of the photoreceptor layers, which together are specific for CEP290-related ciliopathy (total 4 points, PMID: 29398085 and additional details from coauthor, PP4). The variant has been reported to segregate with childhood-onset severe retinal dystrophy through the proband plus at least 4 similarly affected relatives, with the variant present in the compound heterozygous state (PMID:29298085), and in a family with 3 homozygous siblings (PMID:28418496, PP1_Strong). The computational predictor CADD gives a score of 25.9, which is above the ClinGen LCA/eoRD VCEP threshold of ≥25.3 and predicts a damaging effect on CEP290 protein function (PP3). Additionally, the splicing impact predictor SpliceAI gives a score of 0.08, 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 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, PP1_Strong, and PP3. (LCA/eoRD VCEP Specifications for CEP290 Version 1.0.0)

PP1_Strong

The variant has been reported to segregate with childhood-onset severe retinal dystrophy through the proband plus at least 4 similarly affected relatives, with the variant present in the compound heterozygous state (PMID:29298085) and in a family with 3 homozygous siblings (PMID:28418496) (PP1_Strong).

PM3_Strong

This variant has been reported in at least 2 unrelated probands with early-onset severe retinal dystrophy who were homozygous for the variant (1 point, PMIDs: 29398085, 28418496). This variant has also been reported in at least 1 proband with early-onset severe retinal dystrophy who was compound heterozygous with the p.Arg1465Ter variant confirmed in trans (1 point, PMID: 29398085), which was previously classified pathogenic by the ClinGen LCA/eoRD VCEP (2 total points, PM3_Strong).

PM2_Supporting

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

PP4

At least one proband harboring this variant exhibits a phenotype including a diagnosis of LCA (0.5 pts), symptoms present from birth (0.5 pts), severely reduced visual acuity (0.5 pts) and no clear progression in first decade (0.5 pts). Vision was worse under bright light (0.5 pts), night vision always impaired (0.5 pts). Fundi showed widespread outer retinal atrophy with relative sparing of the macula (1 pt). OCT showed only a small region of preservation of the photoreceptor layers. Together these are specific for CEP290-related ciliopathy (total 4 points, PMID: 29398085 and additional details from coauthor, PP4).

PP3

The computational predictor CADD gives a score of 25.9, 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 0.08 for acceptor loss, which is below the ClinGen LCA/eoRD VCEP recommended threshold of ≥0.2 and does not predict a deleterious impact on splicing.

Curation History

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