SCN1A Gene Curation
- Andrea Oza
Analytics
Gene-disease assertions not curated here (add link or write note): There are several additional seizure disorders curated in ClinGen (GEFS+, DEE, and familial hemiplegic migraine). However, this curation is just to document that LOF causes disease for at least Dravet syndrome. Mechanism of disease isn’t described for the other seizure disorder phenotypes.
Disease | Dravet syndrome |
|---|---|
Inheritance | Autosomal dominant |
Prevalence |
Source: |
Rapid or full curation? | Rapid Full |
ClinGen - Definitive for Dravet syndrome by Epilepsy GCEP | |
Clinical Validity Scoring Notes and points | From CLINGEN: Dravet Syndrome was first described in 1978 (Dravet et. al 1978). Dravet syndrome is a severe condition on the genetic epilepsy with febrile seizures plus (GEFS+) spectrum of seizure disorders. Dravet often occurs with loss-of-function variants in SCN1A that arise de novo. SCN1A has been reported in relation to autosomal dominant Dravet Syndrome in numerous publications. Numerous unique variants (missense, frameshift, nonsense, etc.), including the 9 documented here, have been reported in humans (PMIDs: 23808377, 26438699, 30185235, 24412860, 21647847). Evidence supporting this gene-disease pair includes case-level and experimental data. Supporting experimental evidence includes expression, protein interaction, and biochemical function studies as well as mouse models (PMIDs: 16921370, 17537961, 23821540, 16921370, 17928448). More evidence is available in the literature, but the maximum score for genetic and experimental evidence has been reached. In summary, SCN1A is definitively associated with autosomal dominant Dravet Syndrome. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. Gene Clinical Validity Standard Operating Procedures (SOP) - SOP6 Source: |
Clinical Validity Points Total |
Source: |
Clinical Validity Classification Definitive (12pts) Strong (12pts) Moderate (7-11pts) Limited (0.1-6pts) No genetic evidence Refuted Disputed | Definitive Source: |
Molecular Mechanism Loss of function Gain of function Dominant negative Unknown Other | Loss of function Based on ClinGen curation. Supporting NMD+ variants:
|
Penetrance Complete (100%) High (≥80%) Moderate (<80% and >20%) Low (≤20%) (list source/PMID) |
Source: |
Age of Onset Congenital Pediatric Adolescent Adulthood Late adulthood (list source/PMID) |
|
Severity |
|
Clinical Features |
Sources: |
HPO Terms |
|
Gene SOPs & Notes | LINK if SOP is a long document. Short notes if it is easy to digest. eg. Last known truncating variant |
Curation Summary | The SCN1A gene is associated with autosomal dominant seizure disorders, including generalized epilepsy with febrile seizures, Dravet syndrome, developmental and epileptic encephalopathy and familial hemiplegic migraine (PMID: 20301494). |
Case ID, Curator name, Date, Jira ticket link | Andrea Oza 12.21.23 D-061109681-BH-4009-P-A |