Gene Validity Curation

Gene Validity Classification Summary

Gene/Disease Pair:

CLPP : Perrault syndrome 3

HGNC:2084 | MONDO_0013588
Mode of Inheritance: Autosomal recessive inheritance (HP:0000007)
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
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 5
10
11.5
Theunissen TE et al. 2016 Nov 16 (PMID:27899912); Jenkinson EM et al. 2013 Apr 04 (PMID:23541340); Kremer LS et al. 2017 Jun 12 (PMID:28604674);
Two variants (not predicted/proven null) with some evidence of gene impact in trans 1 0-1.5 6
1.5
Demain LA et al. 2017 Feb (PMID:26970254); Jenkinson EM et al. 2013 Apr 04 (PMID:23541340); Lerat J et al. 2016 Dec (PMID:27650058); Ahmed S et al. 2015 May 01 (PMID:25956234); Dursun F et al. 2016 Dec 01 (PMID:27087618);
Segregation Evidence   Summed LOD Family Count 3 3  
Candidate gene sequencing
Exome/genome or all genes sequenced in linkage region 6.26 3
Jenkinson EM et al. 2013 Apr 04 (PMID:23541340);
Total Summed LOD Score 6.26    
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
Jenkinson EM et al. 2013 Apr 04 (PMID:23541340);
Functional Alteration Patient cells 1 0 - 2 2
Non-patient cells 0.5 0 - 1
Models Non-human model organism 2 0 - 4 4 1 1.5 1.5
Gispert S et al. 2013 Dec 15 (PMID:23851121);
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

 


 

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 14 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
10/04/2018
EXPERT CURATION (DATE)
Definitive
03/27/2018
EVIDENCE SUMMARY
The CLPP gene has been associated with autosomal recessive Perrault syndrome using the ClinGen Clinical Validity Framework as of 11/6/2017. This association was made using case-level data only. At least 11 missense, splice site and frameshift variants have been reported in humans. CLPP was first associated with this disease in humans as early as 2007 (Ain et al.). Association is seen in at least 11 probands in 7 publications (23541340, 27087618, 26970254, 27650058, 25956234, 27899912, 28604674). Variants in this gene segregated with disease in 13 additional family members. This gene-disease association is supported by expression studies and a null mouse model with hearing loss and infertility. In summary, CLPP is definitively associated with autosomal recessive Perrault syndrome. This classification was approved by the ClinGen Hearing Loss Working Group on 3/27/2018.