Variant: NM_021007.3:c.4782G>T

CA349036836

Gene: SCN2A

Condition: complex neurodevelopmental disorder

Inheritance Mode: Autosomal dominant inheritance

UUID: 522f61e7-f7fd-4059-903f-8d9216d58b84

Approved on: 2024-11-26

Published on: 2025-02-20

HGVS expressions

NM_021007.3:c.4782G>T
NC_000002.12:g.165386976G>T
CM000664.2:g.165386976G>T
NC_000002.11:g.166243486G>T
CM000664.1:g.166243486G>T
NC_000002.10:g.165951732G>T
NG_008143.1:g.152575G>T
ENST00000631182.3:c.4782G>T
ENST00000375437.7:c.4782G>T
ENST00000636071.2:c.4782G>T
ENST00000636135.1:c.*3101G>T
ENST00000636384.2:c.*2769G>T
ENST00000636662.2:c.*5305G>T
ENST00000636769.1:c.*2724G>T
ENST00000636985.2:c.4386G>T
ENST00000637266.2:c.4782G>T
ENST00000283256.10:c.4782G>T
ENST00000375427.4:c.4782G>T
ENST00000375437.6:c.4782G>T
ENST00000480032.4:n.8213G>T
ENST00000631182.2:c.4782G>T
NM_001040142.1:c.4782G>T
NM_001040143.1:c.4782G>T
NM_021007.2:c.4782G>T
NM_001040142.2:c.4782G>T
NM_001040143.2:c.4782G>T
NM_001371246.1:c.4782G>T
NM_001371247.1:c.4782G>T

Likely Pathogenic

• Met criteria codes: PP3_Moderate PM5_Supporting PM2_Supporting PM6

Expert Panel

Epilepsy Sodium Channel VCEP

Criteria Specification Information

Criteria Specification: ClinGen Epilepsy Sodium Channel Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for SCN2A Version 1.0.0

Evidence submitted by expert panel

Epilepsy Sodium Channel VCEP

The c.4782G>T variant in SCN2A is a missense variant predicted to cause substitution of tryptophan by cysteine at amino acid 1594 (p.Trp1594Cys). The variant has been identified in multiple individuals meeting criteria for complex neurodevelopmental disorder (PM6)(PMID: 35365919, 23603762). It is absent from the population database gnomAD v2.1.1 and v4.1.0 (PM2_Supporting). The computational predictor REVEL gives a score of 0.924, which is above the threshold of 0.773, evidence that correlates with a maximum strength of PP3_Moderate. The same amino acid change (p.Trp1594Cys), resulting from a different nucleotide change [c.4782G>C] (PMID: 34004075, internal lab contributors) is classified as likely pathogenic for complex neurodevelopmental disorder by the ClinGen Epilepsy Sodium Channel VCEP. Additionally, another missense variant in the same codon c.4780T>A, p.Trp1594Arg reaches likely pathogenic based on current criteria (PM5_Supporting). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal dominant complex neurodevelopmental disorder based on the ACMG/AMP criteria applied, as specified by the ClinGen Epilepsy Sodium Channel VCEP: PM6, PM2_Supporting, PP3_Moderate, PM5_Supporting. (version 1.0; November 26, 2024).

Met criteria codes

• PP3_Moderate: REVEL 0.924
• PM5_Supporting: SCN2A p.W1594R c.4780T>A occurs in the same gene with a different amino acid change. This variant has been reported as de novo in 3 cases in the literature and at a clinical laboratory (PM6_Moderate), is absent in gnomAD v2 and v4 (PM2_Supporting), and has a REVEL score of 0.968. In total, this variant gets to Likely Pathogenic using the current VCEP guidelines (v1.0.0). See details below from literature and VCI page for details. There are no other variants reported in paralogous genes for this amino acid position.
• PM2_Supporting: Absent in gnomAD v2 and v4
• PM6: Observed in the literature in 2 probands. 1. PMID: 35365919: Patient ID E43 3yo F. Dx of Ohtahara syndrome. AOO 7days. Focal tonic seizures w/ ~10 clusters per day, developed West syndrome at 4 m, developed nonspecific focal epilepsy at 12 m; ongoing daily sz; profound DD. Parentage not confirmed. PM6 +0.5 2. PMID: 23603762: P506 w/ severe ID, neonatal seizures, polymicrogyria (likely bilateral), & thin corpus callosum. De novo c.4782G>T is a close match hit with parentage not confirmed. Also carries a second de novo alteration RAI1 c.2564T>C, p.L885P. PM6 +0.5 • RAI1 variant could be contributory to the patient's phenotype, but the age of onset is different and variants at this amino acid position all have a consistent congenital and neonatal onset. Discussed with VCEP panel and agree the RAI1 alteration is secondary to patient's phenotype and SCN2A has better overlap with this proband. Total = +1