Gene Validity Curation

Gene Validity Classification Summary

Gene/Disease Pair:

SCN2A : complex neurodevelopmental disorder

HGNC:10588 | MONDO_0100038
Mode of Inheritance: Autosomal dominant inheritance (HP:0000006)
Expert Panel: Epilepsy
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 10
Kodera H et al. 2013 Jul (PMID:23662938); Ogiwara I et al. 2009 Sep 29 (PMID:19786696); Kamiya K et al. 2004 Mar 17 (PMID:15028761); Liu J et al. 2018 Sep 5 (PMID:30185235); Liao Y et al. 2010 Oct 19 (PMID:20956790); Tavassoli T et al. 2014 Mar 20 (PMID:24650168); Nakamura K et al. 2013 Sep 10 (PMID:23935176); Sanders SJ et al. 2012 Apr 4 (PMID:22495306);
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 1
Ogiwara I et al. 2009 Sep 29 (PMID:19786696);
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   Summed LOD Family Count  
Candidate gene sequencing
Exome/genome or all genes sequenced in linkage region
Total Summed LOD Score    
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) 12
Experimental Evidence
Evidence Category Evidence Type Guidelines Points PMIDs/Notes
Default Range Max Count Total Counted
Function Biochemical Function 0.5 0 - 2 2
Protein Interaction 0.5 0 - 2
Expression 0.5 0 - 2 1 0.5
Willsey AJ et al. 2013 Nov 21 (PMID:24267886);
Functional Alteration Patient cells 1 0 - 2 2
Non-patient cells 0.5 0 - 1 2 0.5
Lauxmann S et al. 2018 Dec (PMID:30144217); Ben-Shalom R et al. 2017 Aug 1 (PMID:28256214);
Models Non-human model organism 2 0 - 4 4 2 4 4
Wolff M et al. 2017 May 1 (PMID:28379373); Middleton SJ et al. 2018 July (PMID:29867081);
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
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
> 2 pubs w/ convincing evidence over time (>3 yrs)
Assigned Points 12 5 17 YES
STRONG 12-18
DEFINITIVE 12-18 AND replication over time
Valid contradictory evidence (Y/N)*
Variation in SCN2A was first reported in relation to complex neurodevelopmental disorder in 2001 (Sugawara et al., PMID 11371648); variants in affected individuals were observed in the heterozygous state (consistent with autosomal dominant mode of inheritance), though most cases are de novo. At least 98 variants (e.g. missense, nonsense, frameshift, splice site) have been reported in humans: 8 variants in individuals with infantile seizures and developmental delay, 51 variants in epileptic encephalopathy with infantile seizures and developmental delay, hypotonia, cerebral atrophy, 39 variants with developmental disorder or autism spectrum disorder/intellectual disability (Ben Shalom et al. 2017 PMID 28256214). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, there is insufficient evidence of a difference in molecular mechanisms or inheritance pattern despite genotype:phenotype correlations that may explain the wide phenotypic spectrum observed from SCN2A variation (PMID 28256214,; therefore, we decided to curate all of these entities together under the umbrella term “complex neurodevelopmental disorder.” Of note, this gene has also been implicated in benign infantile familial seizures (MONDO:0011140). These cases will be assessed in a separate curation. Evidence supporting the relationship between SCN2A and complex neurodevelopmental disorder includes case-level data and experimental data. For the purposes of this curation, 11 variants in this gene were scored in the following 8 publications: PMIDs 19786696, 23662938, 15028761, 30185235, 20956790, 24650168, 23935176, 22495306. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. Of note, both loss-of-function and gain-of-function of SCN2A have been observed in experiments with patient variants (PMIDs 28379373, 29867081). This gene-disease association is supported by mouse models, functional alteration, and expression studies (PMIDs 24267886, 30144217, 28256214, 28379373, 29867081). In summary, SCN2A variation is definitively associated with complex neurodevelopmental disorder. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Epilepsy Expert Panel on 5/7/2019 (SOP Version 6).