Gene Validity Curation

CDC14A - hearing impairment and infertile male syndrome

Gene: CDC14A (HGNC:1718)
Classification - 03/11/2020
Disease: hearing impairment and infertile male syndrome (MONDO_0100069)
Mode of Inheritance: Autosomal recessive inheritance (HP:0000007)
Replication over time: NO Contradictory Evidence: NO
Expert Panel: Hearing Loss EP
Evidence Summary: The CDC14A gene has been associated with autosomal recessive hearing impairment and infertile male syndrome (HIIMS) using the ClinGen Clinical Validity Framework as of 1/18/2018. In five families reported in Imtiaz 2017, females homozygous for CDC14A variants had prelingual sensorineural hearing loss, and homozygous males had hearing loss and infertility (29293958). Three families segregated truncating variants predicted to affect all isoforms of the gene. Two families had two different missense variants in the dual-specificity phosphatase domain of CDC14A. One additional family had a third missense variant in this domain, but the fertility status of the affected males could not be determined. There are four mouse models for this syndrome, including one with a predicted deleterious missense variant in the phosphatase domian generated by CRISPR/Cas9. Of note, this gene has also been implicated in autosomal recessive nonsyndromic hearing loss. This has been​ assessed separately. In summary, there is strong evidence to support the association between CDC14A and autosomal recessive hearing impairment and infertile male syndrome (HIIMS)​. Additional reports in humans are needed to reach a definitive classification. This classification was approved by the ClinGen Hearing Loss​ Working Group on 2/26/2018.
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 3
6
9
Imtiaz A et al. 2018 Mar 1 (PMID:29293958);
Two variants (not predicted/proven null) with some evidence of gene impact in trans 1 0-1.5 2
3
Imtiaz A et al. 2018 Mar 1 (PMID:29293958);
Segregation Evidence   Summed LOD Family Count 3 3  
Candidate gene sequencing
Exome/genome or all genes sequenced in linkage region 5.09 2
Imtiaz A et al. 2018 Mar 1 (PMID:29293958);
Total Summed LOD Score 5.09    
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) 12
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
Protein Interaction 0.5 0 - 2
Expression 0.5 0 - 2 2 1
Delmaghani S et al. 2016 Jun 02 (PMID:27259055); Imtiaz A et al. 2018 Mar 1 (PMID:29293958);
Functional Alteration Patient cells 1 0 - 2 2
Non-patient cells 0.5 0 - 1
Models Non-human model organism 2 0 - 4 4 2 6 4
Imtiaz A et al. 2018 Mar 1 (PMID:29293958);
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) 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 12 5 17 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)
Strong
03/11/2020
EXPERT CURATION (DATE)
Strong
03/11/2020
EVIDENCE SUMMARY
The CDC14A gene has been associated with autosomal recessive hearing impairment and infertile male syndrome (HIIMS) using the ClinGen Clinical Validity Framework as of 1/18/2018. In five families reported in Imtiaz 2017, females homozygous for CDC14A variants had prelingual sensorineural hearing loss, and homozygous males had hearing loss and infertility (29293958). Three families segregated truncating variants predicted to affect all isoforms of the gene. Two families had two different missense variants in the dual-specificity phosphatase domain of CDC14A. One additional family had a third missense variant in this domain, but the fertility status of the affected males could not be determined. There are four mouse models for this syndrome, including one with a predicted deleterious missense variant in the phosphatase domian generated by CRISPR/Cas9. Of note, this gene has also been implicated in autosomal recessive nonsyndromic hearing loss. This has been​ assessed separately. In summary, there is strong evidence to support the association between CDC14A and autosomal recessive hearing impairment and infertile male syndrome (HIIMS)​. Additional reports in humans are needed to reach a definitive classification. This classification was approved by the ClinGen Hearing Loss​ Working Group on 2/26/2018.