Gene Validity Curation

Gene Validity Classification Summary

Gene/Disease Pair:

KITLG : nonsyndromic genetic deafness

HGNC:6343 | 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 2.5 2.5
Zazo Seco C et al. 2015 Nov 5 (PMID:26522471);
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
Two variants (not predicted/proven null) with some evidence of gene impact in trans 1 0-1.5
Segregation Evidence   Summed LOD Family Count 2 2  
Candidate gene sequencing
Exome/genome or all genes sequenced in linkage region 4.8 1
Zazo Seco C et al. 2015 Nov 5 (PMID:26522471);
Total Summed LOD Score 4.8    
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) 4.5
Experimental Evidence
Evidence Category Evidence Type Guidelines Points PMIDs/Notes
Default Range Max Count Total Counted
Function Biochemical Function 0.5 0 - 2 2
1.5
Protein Interaction 0.5 0 - 2 1 1
Hemesath TJ et al. 1998 Jan 15 (PMID:9440696);
Expression 0.5 0 - 2 1 0.5
Zazo Seco C et al. 2015 Nov 5 (PMID:26522471);
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
(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 4.5 1.5 6 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)
Limited
10/04/2018
EXPERT CURATION (DATE)
Limited
01/16/2018
EVIDENCE SUMMARY
The KITLG​ gene has been associated with autosomal dominant nonsyndromic hearing loss​ using the ClinGen Clinical Validity Framework as of 1/5/2018​. This association was made using case-level data only. At least 2​ variants, an in-frame indel and nonsense, have been reported in humans. KITLG​ was first associated with this disease in humans as early as 2015​ (Zazo Seco et al.​). Association is seen in at least 2​ probands in 1​ publications (26522471​). Variants in this gene segregated with disease in 9 additional family members. There is evidence for reduced penetrance of a KITLG variant in one family. This gene-disease association is supported by an expression study and a protein interaction assay. 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 1/16/2018.