Gene Validity Classification Summary

Gene/Disease Pair:

SLC26A4 : Pendred syndrome

HGNC:8818 | MONDO_0010134
Mode of Inheritance: Autosomal recessive inheritance (HP:0000007)
Expert Panel: Hearing Loss EP
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
Autosomal Recessive Disease Two variants in trans and at least one de novo or a predicted/proven null variant 2 0-3 12
Everett LA et al. 1997 Dec (PMID:9398842); Yazdanpanahi N et al. 2013 Dec (PMID:24353858); Ben Said M et al. 2012 Jun (PMID:22429511);
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
Yazdanpanahi N et al. 2013 Dec (PMID:24353858);
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) 12
Experimental Evidence
Evidence Category Evidence Type Guidelines Points PMIDs/Notes
Default Range Max Total Counted
Function Biochemical Function 0.5 0 - 2 2
Scott DA et al. 1999 Apr (PMID:10192399); Yoshida A et al. 2002 Jul (PMID:12107249);
Protein Interaction 0.5 0 - 2
Expression 0.5 0 - 2 1
Everett LA et al. 1997 Dec (PMID:9398842); Hosoya M et al. 2016 Sep (PMID:27091614);
Functional Alteration Patient cells 1 0 - 2 2
Non-patient cells 0.5 0 - 1 1
Taylor JP et al. 2002 Apr (PMID:11932316);
Models Non-human model organism 2 0 - 4 4 3 3
Everett LA et al. 2001 Jan 15 (PMID:11152663); Lu YC et al. 2011 July 21 (PMID:21811566);
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 12 6 18 YES
STRONG 12-18
DEFINITIVE 12-18 AND replication over time
Valid contradictory evidence (Y/N)*
The association between SLC26A4 and autosomal recessive Pendred syndrome is well-established and over 500 variants have been reported, including missense, nonsense, frameshift, splice, in-frame indel, and large deletion variants. The hearing loss associated with SLC26A4 is typically congenital, pre-, or peri-lingual in onset and caused by enlarged vestibular aqueduct (EVA). An incomplete partitioning defect of the cochlea may also be present. Goiter and/or hypothyroidism are an incompletely penetrant feature of Pendred syndrome and may not present until the second decade of life (Pryor 2005, Soh 2015). There may be variable expression of the thyroid features, even within families with the same pathogenic variants. Additionally, a large percentage of individuals with hearing loss and EVA lack variants on one or both alleles of SLC26A4. Individuals with a single mutation appear to be less likely to develop the thyroid features, but may have similar recurrence risks as individuals found to harbor two biallelic pathogenic variants (Pryor 2005, Chattaraj 2014). This gene-disease association is supported by animal models, evidence of expression in the ear and thyroid, and in vitro biochemical studies. In summary, SLC26A4 is definitively associated with autosomal recessive Pendred syndrome. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Hearing Loss Working Group on 6/7/2017.