Gene Validity Curation

Gene Validity Classification Summary

Gene/Disease Pair:

SLC17A8 : nonsyndromic genetic deafness

HGNC:20151 | MONDO_0019497
Mode of Inheritance: Autosomal dominant inheritance (HP:0000006)
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 2 3 3
Ryu N et al. 2016 Jan 22 (PMID:26797701); Ryu N et al. 2017 Sep 5 (PMID:28647561);
Proband with other variant type with some evidence of gene impact 0.5 0-1.5 7 2
0.5
0.5
Ruel J et al. 2008 Aug (PMID:18674745);
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   Summed LOD Family Count 1.5 1.5  
Candidate gene sequencing 5.04 1
Ruel J et al. 2008 Aug (PMID:18674745);
Exome/genome or all genes sequenced in linkage region
Total Summed LOD Score 5.04    
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) 5
Experimental Evidence
Evidence Category Evidence Type Guidelines Points PMIDs/Notes
Default Range Max Count Total Counted
Function Biochemical Function 0.5 0 - 2 2
2
Protein Interaction 0.5 0 - 2
Expression 0.5 0 - 2 4 2
Ruel J et al. 2008 Aug (PMID:18674745); Yoshimura H et al. 2014 Mar 27 (PMID:24676347); Obholzer N et al. 2008 Feb 27 (PMID:18305245); Liu H et al. 2014 Aug 13 (PMID:25122905);
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 6 4
Ruel J et al. 2008 Aug (PMID:18674745); Seal RP et al. 2008 Jan 24 (PMID:18215623); Obholzer N et al. 2008 Feb 27 (PMID:18305245);
Cell culture model 1 0 - 2
Rescue Rescue in human 2 0 - 4
Rescue in non-human model organism 2 0 - 4 1
2
Akil O et al. 2012 Jul 26 (PMID:22841313);
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
(0-18)
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
Evidence
> 2 pubs w/ convincing evidence over time (>3 yrs)
Assigned Points 5 6 11 NO
CALCULATED CLASSIFICATION LIMITED 1-6
MODERATE 7-11
STRONG 12-18
DEFINITIVE 12-18 AND replication over time
Valid contradictory evidence (Y/N)*
NO
CALCULATED CLASSIFICATION (DATE)
Moderate
10/02/2018
MODIFY CALCULATED CLASSIFICATION
YES
MODIFIED CLASSIFICATION (DATE)
Strong
10/02/2018
REASON(S) FOR CHANGE
Expert discussion felt this association is Strong.
EXPERT CURATION (DATE)
Strong
09/12/2017
EVIDENCE SUMMARY
The SLC17A8 gene has been associated with autosomal dominant nonsyndromic hearing loss using the ClinGen Clinical Validity Framework as of 10/7/16. This association was made using case-level data. At least 3 variants (a missense, a frameshift and a splice site) have been reported in humans. SLC17A8 was first associated with this disease in humans as early as 2008 (Ruel et al.​). Association is seen in at least 3 probands in 3​ publications (18674745, 26797701, 28647561). Variants in this gene segregated with disease in 21 additional family members. This gene-disease association is supported by a knock-out mouse model, a mouse rescue, and a zebrafish model. In summary, there is strong evidence to support the association between SCL17A8 and autosomal dominant nonsyndromic hearing loss. Additional reports in humans are needed​ to reach a definitive classification. This classification was approved by the ClinGen Hearing Loss Working Group on 9/12/17.