Retinal disorders

Gene: UNC119

I don't know

Comment on list classification: There are three cone-rod dystrophy patients from three unrelated families reported with heterozygous UNC119 variants. However, there is conflicting evidence regarding pathogenicity of the variants. Due to conflicting evidence, this gene should be demoted to Amber for retinal disorders.

Created: 12 Sep 2025, 12:45 p.m. | Last Modified: 12 Sep 2025, 12:45 p.m.

Panel Version: 8.25

There are three individuals reported in literature affected by cone-rod dystrophy, who carry heterozygous UNC119 variants:

35947183 Zenteno et al., 2023 - Patient 1 – 55yo male with cone-rod dystrophy. Mother and aunt had macular degeneration (not genotyped, deceased). Patient heterozygous for c.601G>T; p.(Glu201Ter); sequencing method: WES. GnomAD AF 0.0001167 (admixed American).

23563732 Huang et al., 2013 – Male patient with cone-rod dystrophy, onset of disease at 3yo. Het for c.259G>A p.(Asp87Asn) in UNC119. GnomAD freq 0.00004213, Revel score = 0.49 (Uncertain). Method: sequenced 20 candidate genes only.

11006213 Kobayashi et al., 2000 - Heterozygous c.169A>T; p.(Lys57Ter) was found in a 57-year-old woman with late-onset cone-rod dystrophy (deteriorating vision from age 40). GnomAD allele freq = 0.0002249 including 1 homozygote. Method: PCR DNA sequencing of 5 exons of UNC119 only. A transgenic mouse model, where mouse ortholog unc119 was truncated at amino-acid 57, showed retinal degeneration with marked synaptic and possible transsynaptic degeneration. The authors propose a dominant negative mechanism of disease, over Loss-of-Function.

As outlined by Ronnie Wright, there is conflicting evidence regarding the disease association. The reported variants p.(Asp87Asn) and p.(Lys57Ter) have relatively high allele frequencies in the general population (30910914 Mor & Dror, 2019) and there is scarce evidence of autosomal dominant inheritance in the reported families. In summary, due to the presence of conflicting evidence, this gene should be demoted to Amber for Retinal disorders.

In Gene2Phenotype, UNC119 has a Limited association with UNC119-related cone-rod dystrophy. The gene is associated with autosomal dominant cone-rod dystrophy in OMIM (accessed 20th Aug 2025).

Created: 12 Sep 2025, 12:45 p.m. | Last Modified: 12 Sep 2025, 12:45 p.m.

Panel Version: 8.25

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
retinal disorder, MONDO:0005283; Cone-rod dystrophy 24, OMIM:620342

Publications

• 11006213
• 23563732
• 35947183
• 30910914

I don't know

PMID:30910914 disputes the initial association of UNC119 with inherited retinal disease, in particular commenting on Lys57Ter and its control frequency (one of first UNC119 variants reported in association with IRD, with an equivalent transgenic mouse model supporting the association).

Lys57Ter is present in several patients/families referred for clinical whole genome sequencing in England but it does not appear to be statistically enriched in those referred with retinal dystrophy. Nor do other variants (in particular LoF) in UNC119 in England's Clinical Variant Arc.

Statistical evidence using GnomAD control data suggests a low probability of intolerance to heterozygous loss of function and no evidence of intolerance to heterozygous missense variants.

While the evidence of disease association is disputed/conflicting and only limited/supportive (at best) I'm not sure it is clinically appropriate to report UNC119 variants as causative of IRD or assign a Green rating to the gene. Any UNC119 variants in NHSE/GMS may be best handled by discovery/research groups at a cohort level until such disputed evidence is resolved.

Created: 17 Mar 2025, 3:21 p.m. | Last Modified: 17 Mar 2025, 3:21 p.m.

Panel Version: 7.8

Mode of inheritance
Unknown

Publications

• PMID:30910914

Mode of pathogenicity
Other

The rating of this gene has been updated following NHS Genomic Medicine Service approval.

Created: 8 Mar 2022, 10:43 a.m. | Last Modified: 8 Mar 2022, 10:43 a.m.

Panel Version: 2.245

Comment on list classification: This gene is associated with a relevant phenotype in Gene2Phenotype but not in OMIM. Based on the available evidence there are 2 independent cases with an animal model, therefore there is enough evidence to support a gene-disease association. This gene should be rated Green at the next review.

Created: 17 Feb 2021, 4:25 p.m. | Last Modified: 17 Feb 2021, 4:25 p.m.

Panel Version: 2.168

Green List (high evidence)

Two families reported with cone-rod dystrophy, and a supporting mouse and zebrafish model with retinal degeneration.

Created: 15 Oct 2020, 9:15 a.m. | Last Modified: 15 Oct 2020, 9:15 a.m.

Panel Version: 2.20

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Cone-rod dystrophy

Publications

• 11006213
• 23563732
• 27079236

Red List (low evidence)

unlikely that het LOF is causative

Created: 30 Aug 2019, 2:12 p.m. | Last Modified: 30 Aug 2019, 2:12 p.m.

Panel Version: 1.159

I don't know

Two published incidences - but only one convincing (with functional studies in model organism) - on this basis (a single confirmed incidence) I am not sure that this warrants inclusion in the panel.

Created: 1 Jun 2016, 11:28 a.m.

Phenotypes
Cone rod dystrophy

Publications

• PMID: 11006213 PMID: 23563732

Variants in this GENE are reported as part of current diagnostic practice

This gene is on the Manchester Genetic Retinal Degeneration Conditions panel (covers known genes for isolated progessive retinal degeneration, Leber congenital amaurosis, macular dystrophy, achromatopsia, congenital stationary night blindness as well as the two most common causes of syndromic blindess Usher and Bardet-Biedl syndromes and additional syndromes including Joubert, Senior-Loken, and Cohen syndrome.

Created: 2 Jun 2016, 8:06 a.m.

Comment on list classification: One family study reported in OMIM for cone-rod dystrophy.

Created: 23 Mar 2016, 2:07 p.m.