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  3. SIX5
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Fetal anomalies

Gene: SIX5

Red List (low evidence)
SIX5 (SIX homeobox 5)
EnsemblGeneIds (GRCh38): ENSG00000177045
EnsemblGeneIds (GRCh37): ENSG00000177045
OMIM: 600963, Gene2Phenotype
SIX5 is in 11 panels

3 reviews

Achchuthan Shanmugasundram (Genomics England Curator)

Red List (low evidence)

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

The GMS reviewers noted as follows:
Disputed by ClinGen and now red on most other panels. Variants in the literature have high frequency in gnomad.
Created: 11 Mar 2026, 7:08 p.m. | Last Modified: 11 Mar 2026, 7:22 p.m.
Panel Version: 6.157
Created: 11 Mar 2026, 7:08 p.m.
Last Modified: 11 Mar 2026, 7:22 p.m.
Panel version: 6.157

Arina Puzriakova (Genomics England Curator)

Red List (low evidence)

Comment on list classification: As the evidence for the association of SIX5 with branchio-oto-renal syndrome is disputed, this gene should be considered for demotion to red rating in the next GMS update.
Created: 22 Oct 2025, 1:24 p.m. | Last Modified: 22 Oct 2025, 1:24 p.m.
Panel Version: 6.110
This gene-disease association has been rated as 'DISPUTED' by ClinGen (https://search.clinicalgenome.org/CCID:006145) Multiple families reported but reported variants are high in frequency in population databases, have no evidence of pathogenicity, and/or an alternate cause of disease has later been reported (21280147). Two independent SIX5 mouse models have cataracts and no ear or kidney abnormalities (10802667, 10802668) which are typical of branchio-oto-renal syndrome.
Created: 22 Oct 2025, 1:23 p.m. | Last Modified: 22 Oct 2025, 1:23 p.m.
Panel Version: 6.109
Created: 22 Oct 2025, 1:23 p.m.
Last Modified: 22 Oct 2025, 1:23 p.m.
Panel version: 6.109

Rebecca Foulger (Genomics England curator)

Green List (high evidence)

This gene and phenotype were reviewed during meetings at Great Ormond Street hospital in March 2019. Clinical review and curation was performed by Lyn Chitty, Anna de Burca, Rhiannon Mellis, Richard Scott, Ellen McDonagh and Rebecca Foulger. Outcome of review: Confirmed that phenotype is fetally-relevant: keep on the Fetal anomalies panel as a Green gene.
Created: 4 Apr 2019, 2:03 p.m.
DDG2P rating in original PAGE list: Confirmed for BRANCHIOOTORENAL SYNDROME TYPE 2
Created: 11 Dec 2018, 9:05 a.m.
In the original PAGE file, MOP listed as All missense/in frame.
Created: 8 Nov 2018, 4:45 p.m.

Mode of pathogenicity
Other - please provide details in the comments

Created: 8 Nov 2018, 4:45 p.m.

Panel version: 0.161

Details

Mode of Inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Sources
  • Expert Review Red
  • NHS GMS
  • PAGE DD-Gene2Phenotype
Phenotypes
  • Branchiootorenal syndrome 2, OMIM:610896
Tags
disputed
OMIM
600963
Clinvar variants
Variants in SIX5
Penetrance
None
Panels with this gene

History Filter Activity

11 Mar 2026, Gel status: 1

Removed Tag, Removed Tag

Achchuthan Shanmugasundram (Genomics England Curator)

Tag Q3_25_expert_review was removed from gene: SIX5. Tag Q3_25_demote_red was removed from gene: SIX5.

11 Mar 2026, Gel status: 1

Added New Source, Added New Source, Status Update

Achchuthan Shanmugasundram (Genomics England Curator)

Source NHS GMS was added to SIX5. Source Expert Review Red was added to SIX5. Rating Changed from Green List (high evidence) to Red List (low evidence)

22 Oct 2025, Gel status: 3

Entity classified by Genomics England curator

Arina Puzriakova (Genomics England Curator)

Gene: six5 has been classified as Green List (High Evidence).

22 Oct 2025, Gel status: 3

Added Tag, Added Tag, Added Tag

Arina Puzriakova (Genomics England Curator)

Tag Q3_25_expert_review tag was added to gene: SIX5. Tag disputed tag was added to gene: SIX5. Tag Q3_25_demote_red tag was added to gene: SIX5.

22 Oct 2025, Gel status: 3

Set Phenotypes

Arina Puzriakova (Genomics England Curator)

Phenotypes for gene: SIX5 were changed from BRANCHIOOTORENAL SYNDROME TYPE 2 to Branchiootorenal syndrome 2, OMIM:610896

8 Nov 2018, Gel status: 4

Created, Added New Source, Set mode of inheritance, Set Phenotypes

Rebecca Foulger (Genomics England curator)

gene: SIX5 was added gene: SIX5 was added to Fetal anomalies. Sources: Expert Review Green,PAGE DD-Gene2Phenotype Mode of inheritance for gene: SIX5 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Phenotypes for gene: SIX5 were set to BRANCHIOOTORENAL SYNDROME TYPE 2