Gene Validity Curation

Gene Validity Classification Summary

Gene/Disease Pair:

SIX5 : branchio-oto-renal syndrome

HGNC:10891 | MONDO_0007029
Mode of Inheritance: Autosomal dominant inheritance (HP:0000006)
Expert Panel: Hearing Loss
SOP: Gene Clinical Validity Standard Operating Procedures (SOP), Version 5

Genetic Evidence
Case-Level Data
Evidence Type Case Information Type Guidelines Points PMIDs/Notes
Default Range Max Total Counted
Variant Evidence
Autosomal Dominant or X-linked Disorder Variant is de novo 2 0-3 12
Proband with predicted or proven null variant 1.5 0-2 10
Proband with other variant type with some evidence of gene impact 0.5 0-1.5 7
Hoskins BE et al. 2007 Apr (PMID:17357085); Hwang DY et al. 2014 Jun (PMID:24429398);
Autosomal Recessive Disease Two variants in trans and at least one de novo or a predicted/proven null variant 2 0-3 12
Two variants (not predicted/proven null) with some evidence of gene impact in trans 1 0-1.5
Segregation Evidence Evidence of segregation in one or more families   Sequencing Method 0-3 3
Total LOD Score Canditate Gene Sequencing Exome/Genome or all genes sequenced in linkage region  
2-2.99 0.5 1
3-4.99 1 2
≥5 1.5 3
Case-Control Data
Case-Control Study Type Case-Control Quality Criteria Guidelines Points PMIDs/Notes
Points/Study Max Total Counted
Single Variant Analysis 1. Variant Detection Methodology
2. Power
3. Bias and confounding
4. Statistical Significance
0-6 12
Aggregate Variant Analysis 0-6
Total Genetic Evidence Points (Maximum 12) 0
Experimental Evidence
Evidence Category Evidence Type Guidelines Points PMIDs/Notes
Default Range Max Total Counted
Function Biochemical Function 0.5 0 - 2 2
Hoskins BE et al. 2007 Apr (PMID:17357085);
Protein Interaction 0.5 0 - 2 1
Li S et al. 2004 Jan 23 (PMID:14704431); Ozaki H et al. 2002 (PMID:11950062);
Expression 0.5 0 - 2
Functional Alteration Patient cells 1 0 - 2 2
Non-patient cells 0.5 0 - 1
Models Non-human model organism 2 0 - 4 4
Cell culture model 1 0 - 2
Rescue Rescue in human 2 0 - 4
Rescue in non-human model organism 2 0 - 4
Rescue in cell culture model 1 0 - 2
Rescue in patient cells 1 0 - 2
Total Experimental Evidence Points (Maximum 6) 1.5



Assertion criteria Genetic Evidence (0-12 points) Experimental Evidence
(0-6 points)
Total Points
Replication Over Time (Y/N)
Description Case-level, family segregation, or case-control data that support the gene-disease association Gene-level experimental evidence that support the gene-disease association Sum of Genetic & Experimental
> 2 pubs w/ convincing evidence over time (>3 yrs)
Assigned Points 0 1.5 1.5 NO
STRONG 12-18
DEFINITIVE 12-18 AND replication over time
Valid contradictory evidence (Y/N)*
Hoskins BE et al. 2007 Apr (PMID:17357085); Klesert TR et al. 2000 May (PMID:10802667); Sarkar PS et al. 2000 May (PMID:10802668);
Reported variants are not scorable for the following reasons: higher frequency in gnomAD than the disease prevalence, no evidence of pathogenicity, alternate cause of disease later discovered. Additionally, two mouse models for Six5 have cataracts as a phenotype, and no ear or kidney abnormalities.
The SIX5 gene has been associated with autosomal dominant branchio-oto-renal syndrome using the ClinGen Clinical Validity Framework as of 4/20/2017. This association was made using case-level data only. At least 5 missense variants have been reported in humans. SIX5 was first associated with this disease in humans as early as 2007 (Hoskins et al.). Association has been reported in at least 6 probands in 2 publications (17357085, 24429398), however the 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). This gene-disease association is supported by protein interaction and biochemical function studies (14704431, 17357085, 11950062). While EYA1 and SIX1 gene inactivation in mice leads to ear and kidney abnormalities, two independent SIX5 mouse models have cataracts and no ear or kidney abnormalities (10802667, 10802668). In summary, there is convincing evidence disputing the association between SIX5 and autosomal dominant branchio-oto-renal syndrome. More evidence is needed to either support or refute the role SIX5 plays in this disease. This classification was approved by the ClinGen Hearing Loss Working Group on 1/16/2018.