Gene Validity Classification Summary

Gene/Disease Pair:

PJVK : nonsyndromic genetic deafness

HGNC:29502 | 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 4
8
10.5
Salime S et al. 2017 Oct (PMID:28964305); Collin RW et al. 2007 Jul (PMID:17373699); Zhang QJ et al. 2015 Mar (PMID:25631766);
Two variants (not predicted/proven null) with some evidence of gene impact in trans 1 0-1.5 4
2.5
Delmaghani S et al. 2006 Jul (PMID:16804542); Wu CC et al. 2015 Jul (PMID:26166082); Mujtaba G et al. 2012 Aug 01 (PMID:22617256);
Segregation Evidence   Summed LOD Family Count 1.5 1.5  
Candidate gene sequencing 13.06 3
Delmaghani S et al. 2006 Jul (PMID:16804542); Salime S et al. 2017 Oct (PMID:28964305);
Exome/genome or all genes sequenced in linkage region
Total Summed LOD Score 13.06    
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
2
Protein Interaction 0.5 0 - 2
Expression 0.5 0 - 2 4 2
Delmaghani S et al. 2006 Jul (PMID:16804542); Kazmierczak M et al. 2017 Mar 29 (PMID:28209736); Delmaghani S et al. 2015 Nov 05 (PMID:26544938); Harris SL et al. 2017 Mar 06 (PMID:28089576);
Functional Alteration Patient cells 1 0 - 2 2
Non-patient cells 0.5 0 - 1
Models Non-human model organism 2 0 - 4 4 4 8 4
Delmaghani S et al. 2006 Jul (PMID:16804542); Kazmierczak M et al. 2017 Mar 29 (PMID:28209736); Delmaghani S et al. 2015 Nov 05 (PMID:26544938); Harris SL et al. 2017 Mar 06 (PMID:28089576);
Cell culture model 1 0 - 2
Rescue Rescue in human 2 0 - 4
Rescue in non-human model organism 2 0 - 4 1
2
Delmaghani S et al. 2015 Nov 05 (PMID:26544938);
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
12/06/2018
EXPERT CURATION (DATE)
Definitive
12/19/2017
EVIDENCE SUMMARY
The relationship between DFNB59 (aka PJVK) and autosomal recessive nonsyndromic genetic deafness was evaluated using the ClinGen Clinical Validity Framework as of 11/17/2017. Variants in PJVK were first reported in humans with this disease as early as 2006 (Delmaghani et al., PMID 16804542). At least 8 unique variants (missense, in-frame indel, nonsense, frameshift) have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data, animal models, and expression studies that help elucidate the role of PJVK in the peroxisomes of inner ear hair cells and neurons (PMIDs: 16804542, 26166082, 22617256, 28964305, 17373699, 25631766). Variants in this gene have been reported in at least 8 probands in 14 publications. Variants in this gene segregated with disease in more than 33 additional family members.More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism for disease is hypothesized to be that the PJVK gene is critical to the "regulation of peroxisomal dynamics and the antioxidant defense triggered by noise exposure in hair cells and auditory neurons of the inner ear"(PMID: 26544930). In summary, DFNB59 is definitively associated with ARNSHL. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Hearing Loss Working Group on 12/19/2017.