Gene Validity Curation

Gene Validity Classification Summary

Gene/Disease Pair:

AIFM1 : X-linked hereditary sensory and autonomic neuropathy with deafness

HGNC:8768 | MONDO_0010378
Mode of Inheritance: X-linked inheritance (HP:0001417)
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 2
4
4
Miyake N et al. 2017 Dec (PMID:28842795);
Proband with predicted or proven null variant 1.5 0-2 10 1 1.5 1.5
Ghezzi D et al. 2010 Apr 9 (PMID:20362274);
Proband with other variant type with some evidence of gene impact 0.5 0-1.5 7 10
4.5
4.5
Zong L et al. 2015 Aug (PMID:25986071); Rinaldi C et al. 2012 Dec 7 (PMID:23217327); Hu B et al. 2017 Dec (PMID:28888069); Sancho P et al. 2017 Dec (PMID:28975462); Miyake N et al. 2017 Dec (PMID:28842795);
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 3 3  
Candidate gene sequencing
Exome/genome or all genes sequenced in linkage region 5.41 2
Zong L et al. 2015 Aug (PMID:25986071);
Total Summed LOD Score 5.41    
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
0.5
Protein Interaction 0.5 0 - 2
Expression 0.5 0 - 2 1 0.5
Zong L et al. 2015 Aug (PMID:25986071);
Functional Alteration Patient cells 1 0 - 2 2 3
2
2
Ghezzi D et al. 2010 Apr 9 (PMID:20362274); Rinaldi C et al. 2012 Dec 7 (PMID:23217327);
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) 2.5

 


 

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 2.5 14.5 YES
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)
Definitive
10/05/2018
EXPERT CURATION (DATE)
Definitive
07/09/2018
EVIDENCE SUMMARY
The AIFM1 gene has been associated with X-linked disease that presents with a spectrum of auditory and sensory neuropathy phenotypes using the ClinGen Clinical Validity Framework as of 7/5/18. This association was made using case-level data. At least 12 variants, including missense variants and an in-frame deletion, have been reported in humans. Association is seen in at least 12 probands in 6 publications (25986071, 20362274, 23217327, 28888069, 28975462, 28842795), which includes two de novo cases. Variants in this gene segregated with disease in >25 additional family members. The AIFM1 protein is an apoptosis-inducing factor, and multiple patient-cell studies have shown a sensitivity to apoptosis (20362274, 23217327). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in molecular mechanism in cases reported as isolated hearing loss. In summary, AIFM1​ is definitively associated with an X-linked auditory and sensory neuropathy spectrum. This classification was approved by the ClinGen Hearing Loss Working Group on 7/9/2018.