Gene Validity Curation

Gene Validity Classification Summary

Gene/Disease Pair:

SLC26A5 : nonsyndromic genetic deafness

HGNC:9359 | MONDO_0019497
Mode of Inheritance: Autosomal recessive inheritance (HP:0000007)
Expert Panel: Hearing Loss
SOP: Gene Clinical Validity Standard Operating Procedures (SOP), Version 6

Genetic Evidence
Case-Level Data
Evidence Type Case Information Type Guidelines Points PMIDs/Notes
Default Range Max Count 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
Autosomal Recessive Disease Two variants in trans and at least one de novo or a predicted/proven null variant 2 0-3 12 2
Mutai H et al. 2013 Oct 28 (PMID:24164807); Liu XZ et al. 2003 May 15 (PMID:12719379);
Two variants (not predicted/proven null) with some evidence of gene impact in trans 1 0-1.5 2
Toth T et al. 2007 Oct (PMID:17786286); Sloan-Heggen CM et al. 2016 Apr (PMID:26969326);
Segregation Evidence   Summed LOD Family Count  
Candidate gene sequencing
Exome/genome or all genes sequenced in linkage region
Total Summed LOD Score    
Case-Control Data
Case-Control Study Type Case-Control Quality Criteria Guidelines Points PMIDs/Notes
Points/Study Max Count Points 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) 2
Experimental Evidence
Evidence Category Evidence Type Guidelines Points PMIDs/Notes
Default Range Max Count Total Counted
Function Biochemical Function 0.5 0 - 2 2 3
Zheng J et al. 2000 May 11 (PMID:10821263); Oliver D et al. 2001 Jun 22 (PMID:11423665); Mio K et al. 2008 Jan 11 (PMID:17998209);
Protein Interaction 0.5 0 - 2
Expression 0.5 0 - 2 3 1.5
Liu XZ et al. 2003 May 15 (PMID:12719379); Zheng J et al. 2000 May 11 (PMID:10821263); Hosoya M et al. 2016 Sep (PMID:27091614);
Functional Alteration Patient cells 1 0 - 2 2
Non-patient cells 0.5 0 - 1
Models Non-human model organism 2 0 - 4 4 3 4 4
Liberman MC et al. 2002 Sep 19 (PMID:12239568); Fang J et al. 2012 Feb (PMID:21954035); Dallos P et al. 2008 May 8 (PMID:18466744);
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) 6



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 2 6 8 NO
STRONG 12-18
DEFINITIVE 12-18 AND replication over time
Valid contradictory evidence (Y/N)*
Strong functional evidence in mice, but lack of convincing human cases.
The SLC26A5 gene has been associated with autosomal recessive nonsyndromic hearing loss (ARNSHL) using the ClinGen Clinical Validity Framework as of 3/22/2017. This association was made using case-level data and experimental data. At least 6 variants (missense, nonsense, 5' UTR splicing) have been reported in humans. SLC26A5 was first associated with this disease in humans as early as 2003 (Liu et al.). Association is seen in at least 5 probands in 5 publications, however the association was only scored in one publication because other variants didn't have sufficient evidence for pathogenicity (12719379, 17786286, 19492055, 26969326, 24164807). Variants in this gene segregated with disease in 1 additional family member. The mechanism for disease is presumably homozygous loss of function based on evidence derived from one human case and mouse studies (24164807, 18466744, 12239568). This gene-disease association is supported by mouse models, biochemical function studies and expression studies (12239568, 10821263, 11423665, 12719379, 18466744, 27091614, 17998209). There is strong evidence that loss of SLC26A5 causes hearing loss in mice, there is limited evidence in humans, despite the gene being discovered in 2000. Researchers have posited that humans have a compensatory mechanism that mice do not have (Hosoya 2016). In summary, there is limited evidence to support this gene-disease association. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease association. This classification was approved by the ClinGen Hearing Loss Working Group on 12/19/2017.