Gene Validity Curation

Gene Validity Classification Summary

Gene/Disease Pair:

SCN9A : epilepsy

HGNC:10597 | MONDO_0005027
Mode of Inheritance: Autosomal dominant inheritance (HP:0000006)
Expert Panel: Epilepsy
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 0 0
Yang C et al. 2018 Mar 2. (PMID:29500686);
Proband with other variant type with some evidence of gene impact 0.5 0-1.5 7
0.8
0.8
Singh NA et al. 2009 Sep (PMID:19763161); Mulley JC et al. 2013 Sep (PMID:23895530); Allen NM et al. 2016 Apr 23 (PMID:27504264); Cen Z et al. 2017 Aug (PMID:28704742); Yang C et al. 2018 Mar 2. (PMID:29500686);
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 Evidence of segregation in one or more families   Sequencing Method 0-3 3
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) 3.8
Experimental Evidence
Evidence Category Evidence Type Guidelines Points PMIDs/Notes
Default Range Max Total Counted
Function Biochemical Function 0.5 0 - 2 2
Protein Interaction 0.5 0 - 2
Expression 0.5 0 - 2
Functional Alteration Patient cells 1 0 - 2 2
Non-patient cells 0.5 0 - 1
Models Non-human model organism 2 0 - 4 4 0.5 0.5
Singh NA et al. 2009 Sep (PMID:19763161); Nassar MA et al. 2004 Aug 24 (PMID:15314237);
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) 0.5

 


 

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 3.8 0.5 4.3 NO
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)
Limited
06/15/2018
EXPERT CURATION (DATE)
Limited
06/15/2018
EVIDENCE SUMMARY
The SCN9A gene has been associated with autosomal dominant epilepsy (MONDO:0005027) using the ClinGen Clinical Validity Framework as of 6/5/2018. This association was made using case-level data only. At least 4 missense variants have been reported in humans. SCN9A was first associated with this disease in humans as early as 2009 (Singh et al.). Association is seen in at least 4 probands in 2 publications (Singh et al. 2009, Mulley et al. 2013). Variants in this gene segregated with disease in 21 additional family members. This gene-disease association is weakly supported by a mouse model with a homozygous p.Asn641Tyr variant knock-in. In summary, there is limited evidence to support this gene-disease association. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease association.