Gene Validity Classification Summary

Gene/Disease Pair:

ABHD12 : PHARC syndrome

HGNC:15868 | MONDO_0012984
Mode of Inheritance: Autosomal recessive inheritance (HP:0000007)
Expert Panel: Hearing Loss EP
SOP: Gene Clinical Validity Standard Operating Procedures (SOP), Version 5

Genetic Evidence
Case-Level Data
Evidence Type Case Information Type Guidelines Points PMIDs/Notes
Default Range Max 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
12
12
Fiskerstrand T et al. 2010 Sep 10 (PMID:20797687); Yoshimura H et al. 2015 May (PMID:25743180); Eisenberger T et al. 2012 Sep 2 (PMID:22938382); Lerat J et al. 2017 Jun (PMID:28448692);
Two variants (not predicted/proven null) with some evidence of gene impact in trans 1 0-1.5
Segregation Evidence Evidence of segregation in one or more families   Sequencing Method 0-3 3
 
Total LOD Score Canditate Gene Sequencing Exome/Genome or all genes sequenced in linkage region  
2-2.99 0.5 1
3-4.99 1 2
≥5 1.5 3
Case-Control Data
Case-Control Study Type Case-Control Quality Criteria Guidelines Points PMIDs/Notes
Points/Study Max Total 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 Total Counted
Function Biochemical Function 0.5 0 - 2 2
0.5
Protein Interaction 0.5 0 - 2
Expression 0.5 0 - 2 0.5
Tingaud-Sequeira A et al. 2017 Feb (PMID:27890673);
Functional Alteration Patient cells 1 0 - 2 2
1
1.5
Chen DH et al. 2013 Dec (PMID:24027063);
Non-patient cells 0.5 0 - 1 0.5
Tingaud-Sequeira A et al. 2017 Feb (PMID:27890673);
Models Non-human model organism 2 0 - 4 4 2 4
Tingaud-Sequeira A et al. 2017 Feb (PMID:27890673);
Cell culture model 1 0 - 2
Rescue Rescue in human 2 0 - 4
Rescue in non-human model organism 2 0 - 4
2
Tingaud-Sequeira A et al. 2017 Feb (PMID:27890673);
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 12 6 18 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
06/28/2018
EXPERT CURATION (DATE)
Definitive
06/28/2018
EVIDENCE SUMMARY
The ABHD12 gene has been associated with autosomal recessive PHARC syndrome using the ClinGen Clinical Validity Framework as of 6/26/18. This association was made using case-level data only. At least 6 variants (nonsense, frameshift, large deletion) have been reported in humans. ABHD12 was first associated with this disease in humans as early as 2010 (Fickerstrand et al.). Association is seen in at least 6 probands in 5 publications (20797687, 25743180, 22938382, 28448692). Variants in this gene segregated with disease in 2 additional family members (20797687). More evidence is available in the literature, but the maximum score for genetic evidence and/or experimental evidence (12 pts.) has been reached. This gene-disease association is supported by a zebrafish model and additional functional assays. In summary, ABHD12 is definitively associated with autosomal recessive PHARC syndrome. This classification was approved by the ClinGen Hearing Loss Working Group on 6/26/2018.