Retinal disorders

Gene: PDE6H

I don't know

Comment on list classification: As reviewed by Ronnie Wright, the rating for this gene should remain amber. This is because there is only one variant reported across multiple unrelated patients displaying phenotypic variability and without compelling functional evidence.

Created: 9 Oct 2025, 4:24 p.m. | Last Modified: 9 Oct 2025, 4:24 p.m.

Panel Version: 8.39

There is only one homozygous PDE6H variant (p.Ser12Ter) reported to be identified from multiple unrelated individuals. Although this variant has been reported in three unrelated families with cone dysfunction, there are at least three other families reported with incomplete achromatopsia, where limited clinical information was available and cone dysfunction was not reported.

The mouse model also failed to replicate the human phenotype.

Created: 9 Oct 2025, 4:21 p.m. | Last Modified: 9 Oct 2025, 4:24 p.m.

Panel Version: 8.39

Comment on phenotypes: OMIM phenotype accessed on 09 September 2025.

Created: 9 Oct 2025, 4:14 p.m. | Last Modified: 9 Oct 2025, 4:14 p.m.

Panel Version: 8.38

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Achromatopsia 6, OMIM:610024; achromatopsia 6, MONDO:0800197

Publications

• 22901948
• 25739440
• 27472364
• 35567543
• 36980963

I don't know

NM_006205.2(PDE6H):c.35C>G p.(Ser12Ter) 'nonsense' variant appears to be the only variant with any significant evidence in favour of pathogenicity to date.
This variant was recently reported (Exomiser prioritised) when homozygous in a patient with 'cone dystrophy' referred in to the genomic medicine service (no further specificity for the phenotype declared and available to referring clinician at time of MDT/report)

No other nonsense variants reported in this gene (as a proven cause for recessive ACHM6) and it is possible that Ser12Ter is insensitive to NMD due to its start proximal location (although nearest in frame Methionine is way downstream and protein is only 83aa residues in length).

There is evidence of segregation for c.35C>G p.(Ser12Ter) in some families (PMID: 22901948, PMID: 27472364) but in other homozygous individuals declared to be affected, the retinal/ophthalmic phenotype isn't obviously cone related/ACHM6 (PMID: 35567543)

The lack of certainty over LoF, the lack of other plausibly pathogenic variants in this gene, and the Ser12Ter mouse model failing to recapitulate disease means the 'strong' evidence for clinical validity assigned in G2P is debatable. However, observations of c.35C>G p.(Ser12Ter) at least, should be considered carefully for reporting.

Created: 19 Sep 2025, 1:31 p.m. | Last Modified: 19 Sep 2025, 1:31 p.m.

Panel Version: 8.28

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Publications

• PMID: 22901948

Green List (high evidence)

I don't know

PMID: 22901948 reported on 3 patients from 2 unrelated families (Dutch and Belgium) who have incomplete achromatopsia who also have the same variant in PDE6H (missense variant the causes a premature termination). Haplotype analysis for this region suggested that the variant may be from a founder effect.

PMID: 25739440 reported on a Pde6h knockout mouse model. However, the model failed to replicate the human phenotype as it appears that the mouse showed normal retinal tissue. The authors suggest "species-to-species differences in the vulnerability of biochemical and neurosensory pathways of the visual signal transduction system".

Taken together with my previous review, there is still currently not enough evidence to promote this gene to green status.

Created: 29 Aug 2019, 12:15 p.m. | Last Modified: 29 Aug 2019, 12:15 p.m.

Panel Version: 1.149

Comment on list classification: Promoted from red to amber. PDE6H is associated with a phenotype in OMIM and is probably associated with a phenotype in Gene2Phenotype. There is currently only 1 case reporting on 2 siblings with retinal cone dystrophy who has a variant in PDE6H (PMID: 15629837). Therefore, there is currently not enough evidence to support promoting this gene to a green status.

Created: 3 Apr 2019, 1:32 p.m.

Phenotypes
Achromatopsia 6, 610024

Publications

• 22901948
• 25739440