Gene Validity Curation

Gene Validity Classification Summary

Gene/Disease Pair:

SERPINB6 : nonsyndromic genetic deafness

HGNC:8950 | MONDO_0019497
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 2
3
3
Sirmaci A et al. 2010 May 14 (PMID:20451170); Kim NK et al. 2015 Nov (PMID:25719458);
Two variants (not predicted/proven null) with some evidence of gene impact in trans 1 0-1.5
Segregation Evidence   Summed LOD Family Count 1.5 1.5  
Candidate gene sequencing 5 1
Sirmaci A et al. 2010 May 14 (PMID:20451170);
Exome/genome or all genes sequenced in linkage region
Total Summed LOD Score 5    
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) 4.5
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
Sirmaci A et al. 2010 May 14 (PMID:20451170);
Functional Alteration Patient cells 1 0 - 2 2
0.5
Non-patient cells 0.5 0 - 1 1 0.5
Sirmaci A et al. 2010 May 14 (PMID:20451170);
Models Non-human model organism 2 0 - 4 4 1 3.5 3.5
Tan J et al. 2013 Jul (PMID:23669344);
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 4.5 5 9.5 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)
Moderate
12/04/2018
EXPERT CURATION (DATE)
Moderate
04/24/2018
EVIDENCE SUMMARY
The relationship between SERPINB6 and autosomal recessive nonsyndromic hearing loss (ARNSHL) was evaluated using the ClinGen Clinical Validity Framework as of 10/5/2017. Variants in SERPINB6 were first reported in humans with this disease as early as 2010 (Sirmaci et al., PMID: 20451170). At least 4 unique variants (nonsense, frameshift, splicing) have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data, segregation data, and mouse model, functional alteration of a variant in non-patient cells, as well as expression studies (PMIDs: 23669344, 20451170). Variants in this gene have been reported in at least 3 probands in 5 publications (PMID: 20451170, 23669344, 25817395, 25719458, 21117948). Variants in this gene segregated with disease in 4 additional family members. The mechanism of disease is homozygous loss of function leads to progressive cellular degeneration within the cochlea beginning with hair cells and then the primary auditory neurons, and finally the fibrocytes in the lateral wall (PMID: 23669344). This gene-disease association is supported by a In summary, SERPINB6 is definitively associated with ARNSHL. This classification was approved by the ClinGen ARNSHL Working Group on 4/24/2018. (SOP Version 5).