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SCN1A Gene Curation

SCN1A Gene Curation

Owned by Andrea Oza
2023-12-21
3 min read

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

Disease

Dravet syndrome

Inheritance

Autosomal dominant

Prevalence

Orphanet

Medline Plus Genetics

 

Source:

Rapid or full curation?

Rapid
Full

ClinGen / GenCC / BabySeq / HGMD / OMIM

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

Embryonic lethal - presence of a pathogenic variant or variants is not compatible with life. The penetrance must be complete.
Severe - presence of a pathogenic variant or variant(s) results in significantly reduced fitness. The penetrance must be complete or high.
Moderate - significant morbidity or mortality due to clinical features, but fitness may not be reduced, or penetrance is reduced.
Mild - Presence of a variant or variant(s) is not associated with reduced fitness, no significant morbidity or mortality, and/or penetrance is low.
None - presence of a variant results in no phenotype. An example is recessive disorders in which no phenotype is reported in carriers.

 

Clinical Features

 

Sources:

HPO Terms

https://hpo.jax.org/app/

 

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 @GENE@ is associated with @inheritance pattern@ @condition@, which is characterized by @clinical features@ (PMIDs).

- Variable expression or severity:
The severity and expressivity of the disorder is highly variable, even within families.
- If multiple conditions associated with the gene:
It has also been associated with @inheritance pattern@ @condition@, which is characterized by @clinical features@ (PMIDs).

- Limited evidence gene: The PCNA gene has been reported in individuals with early onset autosomal recessive ataxia (PMID: 33426167, 24911150), however, evidence supporting this gene-dIsease relationship is limited

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

 

 

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