Gene Validity Classification Summary

Gene/Disease Pair:

CEMIP : nonsyndromic genetic deafness

HGNC:29213 | MONDO_0019497
Mode of Inheritance: Autosomal recessive inheritance (HP:0000007)
Expert Panel: Hearing Loss EP
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
Two variants (not predicted/proven null) with some evidence of gene impact in trans 1 0-1.5
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) 0
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
Expression 0.5 0 - 2 3 1.5
Abe S et al. 2003 Oct 24 (PMID:14577002); Hosoya M et al. 2016 Jun 14 (PMID:27403418); Usami S et al. 2008 Jun 12 (PMID:18448257);
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 0 1.5 1.5 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
01/02/2019
MODIFY CALCULATED CLASSIFICATION
YES
MODIFIED CLASSIFICATION (DATE)
Disputed
01/02/2019
REASON(S) FOR CHANGE
Only one paper claims to have found pathogenic variants in the gene in patients with NSHL (Abe et al. 2003 PMID 14577002). The study offered little evidence for the pathogenicity of the variants other than their absence from controls. In the absence of convincing genetic evidence, the association between KIAA1199 and ARNSHL is Disputed.
EXPERT CURATION (DATE)
Disputed
07/17/2018
EVIDENCE SUMMARY
KIAA1199 (CEMIP) was first reported in relation to autosomal recessive nonsyndromic hearing loss in 2003 (Abe et al., PMID: 14577002). At least 1 synonymous and 3 missense variants have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data and experimental data. Two probands were noted to have affected siblings, however these siblings were not sequenced or well phenotyped. One individual was reported as compound heterozygous, and shown to have inherited one variant from each unaffected parent. The other 3 cases are reported as heterozygous, with no inheritance information or parental sequencing. This gene-disease association is supported by expression studies that show the gene to be expressed in the cochlea of the mouse, rat and marmoset. In summary, there is no convincing genetic evidence supporting the association between KIAA1199 and nonsyndromic hearing loss, so this association is disputed. More evidence is needed to either support or refute the role KIAA1199 plays in this disease. This classification was approved by the ClinGen Hearing Loss Working Group on 7/17/2018.