SCN1A

Inheritance Pattern: AD

Disease ID:MONDO:0011461

Submitter: G2P

Inheritance Pattern: AD

Disease ID:MONDO:0017385

Submitter: Orphanet

Inheritance Pattern: AD

Disease ID:MONDO:0011794

Submitter: Orphanet

Inheritance Pattern: AD

Disease ID:MONDO:0018214

Submitter: PanelApp Australia

Inheritance Pattern: AD

Disease ID:MONDO:0100135

Submitter: PanelApp Australia

Inheritance Pattern: AD

Disease ID:MONDO:0018925

Submitter: Orphanet

Inheritance Pattern: AD

Disease ID:MONDO:0016532

Submitter: Orphanet

Inheritance Pattern: AD

Disease ID:MONDO:0012320

Submitter: Ambry Genetics

Inheritance Pattern: AD

Disease ID:MONDO:0100062

Submitter: ClinGen

*SCN1A* was first reported in relation to developmental and epileptic encephalopathy (DEE) in 2017 (Sadleir et al.) Per criteria outlined by the ClinGen Lumping and Splitting guidelines, we found differences in molecular mechanism and phenotypic variability. Therefore, the following disease entities have been split into multiple disease entities: developmental and epileptic encephalopathy 6B, non-Dravet (MIM:619317), Dravet syndrome (MIM:607208), febrile seizures, familial, 3A (MIM:604403), generalized epilepsy with febrile seizures plus, type 2 (MIM:604403), and migraine, familial hemiplegic, 3 (MIM:609634). Split curations for AD Dravet syndrome, AD familial hemiplegic migraine, and AD generalized epilepsy with febrile seizures plus have been curated separately. *SCN1A* has been reported with a variety of phenotypes from generalized epilepsy with febrile seizures plus (GEFS+) to Dravet syndrome. Patients who present with DEE tend to have increased phenotypic severity and an earlier age of onset. In contrast to Dravet syndrome and GEFS+, variants associated with DEE lead to a gain of function instead of loss of function. Individuals with this phenotype typically begin to have seizures at <3 months of age, have profound developmental impairment, and have been reported with movement disorders including choreoathetosis, dystonia, and perioral hyperkinesia. Epileptic spasms are also noted. Missense variants have been primarily reported in association with this phenotype, most notably p.Thr226Met (c.677C>T), a recurrent variant identified as *de novo* in several individuals with similar features (PMIDs: 24776920, 26482601, 28794249, 31257984, 31176277). Evidence supporting this gene-disease pair includes case-level and experimental data. Supporting experimental evidence has been reported in a patch-clamp cell culture model (PMID: 30779207). In summary, there is definitive evidence to support the relationship between *SCN1A* and autosomal dominant developmental and epileptic encephalopathy. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. This gene-disease pair was originally evaluated by the Epilepsy GCEP on August 17, 2021. It was reevaluated on December 16, 2025. As a result of this reevaluation, the classification changed from strong to definitive as three years has passed from the original discovery publication date. No additional evidence was added as a result of this recuration.

Inheritance Pattern: AD

Disease ID:MONDO:0100079

Submitter: Ambry Genetics

Inheritance Pattern: AD

Disease ID:MONDO:0011461

Submitter: Ambry Genetics

Inheritance Pattern: AD

Disease ID:MONDO:0018214

Submitter: Orphanet

Inheritance Pattern: Unknown

Disease ID:MONDO:0016025

Submitter: Orphanet

Inheritance Pattern: AD

Disease ID:MONDO:0100062

Submitter: PanelApp Australia

Inheritance Pattern: AD

Disease ID:MONDO:0000700

Submitter: ClinGen

Familial Hemiplegic Migraine (FHM) is a rare autosomal dominant disorder characterized by episodes of migraines with aura and associated hemiplegic attacks. Three genes, CACNA1A, ATP1A2, and SCN1A, have been associated with FHM1, FHM2, and FHM3, respectively. Additional phenotypes such as epilepsy and elicited repetitive daily blindness may be present in some FHM3 patients; however, other phenotypes such as ataxia and intellectual disability reported in FHM1-2 are rare in FHM3. The penetrance of FHM3 is close to 100%. FHM was first reported to be associated with SCN1A in 2005 in a study that identified a SCN1A variant segregating with FHM in three families (Dichgans et al. 2005 PMID: 16054936). Since then, 12 missense variants in SCN1A have been reported to be associated with FHM, including one de novo variant (PMID: 27155821). One of the 11 inherited variants (c.3521C>G; p.Thr1174Ser in NM_001165963.1) has a relatively high frequency in the general population, and is considered a benign polymorphism. The remaining 10 inherited variants and the de novo variant are rare variants not observed in gnomAD version 2.11. The 10 inherited rare variants from 16 families have been reported in 11 studies (16054936, 17397047, 19332696, 29145747, 30498473, 19220312, 24707016, 26763045, 26747084, 27919014, 30038559). Of the 16 families, 11 were given points ranging from 0.1 to 0.5 based on case-level and experimental data. A summed LOD score of 8.61 was calculated from the combined three families in the seminal paper as well as two other families (16054936, 17397047, 19332696). Supporting experimental evidence includes expression and biochemical functional studies (17537961). The accepted mechanism of hemiplegic migraine aura is cortical spreading depression, and mouse models of FHM1 and FHM2 support this theory. Since effects of FHM3 variants in SCN1A are often complex and diverse, the exact mechanisms by which defects in SCN1A could cause cortical spreading depression are unclear; however, SCN1A expression in axonal segments such as axon initial segments and the nodes of Ranvier, and the function in maintenance of action potentials are consistent with SCN1A’s role in neuronal activity and brain excitability, processes related to cortical spreading depression. In summary, a score of 6.5 was given to genetic evidence, and 1 to experimental evidence, reaching 7.5 in total. SCN1A’s association with FHM is moderate.

Inheritance Pattern: AD

Disease ID:MONDO:0018214

Submitter: ClinGen

Generalized epilepsy with febrile seizures plus (GEFS+) is a rare autosomal dominant, familial condition with incomplete penetrance and variable expressivity. It includes a spectrum from commonly mild (such as febrile seizure alone) to rarely severe (including medically treatable generalized epilepsy, intractable generalized epilepsy, or in some cases Dravet syndrome) epilepsy. Individuals with GEFS+ often have febrile seizures (or FS+) in early childhood, followed by occasional tonic, clonic, myoclonic, or absence seizures that respond to medication and remit by late childhood or early adolescence. Intermediate phenotypes with myoclonic, absence, or focal epilepsy are also included. More than 95% of individuals with GEFS+ have a parent with the same SCN1A pathogenic variant (Gennaro et al, 2003); however, the risk of developing seizures is less than 100% because of reduced penetrance, estimated to be 70% for the GEFS+ phenotype (Bonanniet al, 2004). In summary, SCN1A is definitively associated with Generalized Epilepsy with Febrile Seizures Plus. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.

Inheritance Pattern: AD

Disease ID:MONDO:0100079

Submitter: Laboratory for Molecular Medicine

This gene-disease relationship has undergone rapid assessment. Classifications are based on preliminary review of gene-disease validity during analysis of genomic sequencing results.

Inheritance Pattern: AD

Disease ID:MONDO:0100079

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AD

Disease ID:MONDO:0012320

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AD

Disease ID:MONDO:0008779

Submitter: Franklin by Genoox

Whole-exome sequencing was performed from DNA of the index case of AMC families. Heterozygous missense variants in SCN1A (p.Leu893Phe, p.Ala989Thr, p.Ile236Thr) were identified in three patients, all three mutation occurd de novo.

Inheritance Pattern: AD

Disease ID:MONDO:0011461

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AD

Disease ID:MONDO:0100135

Submitter: 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.