Evidence Repository - Clinical Genome Resources

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Variant: NM_001040142.2(SCN2A):c.4782G>C (p.Trp1594Cys)

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CA16603919

383825 (ClinVar)

Gene: SCN2A

Condition: complex neurodevelopmental disorder

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 6cd56d8c-7204-4ecb-b20d-06066ea55d7a

Approved on: 2024-11-26

Published on: 2025-02-20

HGVS expressions

NM_001040142.2:c.4782G>C

NM_001040142.2(SCN2A):c.4782G>C (p.Trp1594Cys)

NC_000002.12:g.165386976G>C

CM000664.2:g.165386976G>C

NC_000002.11:g.166243486G>C

CM000664.1:g.166243486G>C

NC_000002.10:g.165951732G>C

NG_008143.1:g.152575G>C

ENST00000631182.3:c.4782G>C

ENST00000375437.7:c.4782G>C

ENST00000636071.2:c.4782G>C

ENST00000636135.1:c.*3101G>C

ENST00000636384.2:c.*2769G>C

ENST00000636662.2:c.*5305G>C

ENST00000636769.1:c.*2724G>C

ENST00000636985.2:c.4386G>C

ENST00000637266.2:c.4782G>C

ENST00000283256.10:c.4782G>C

ENST00000375427.4:c.4782G>C

ENST00000375437.6:c.4782G>C

ENST00000480032.4:n.8213G>C

ENST00000631182.2:c.4782G>C

NM_001040142.1:c.4782G>C

NM_001040143.1:c.4782G>C

NM_021007.2:c.4782G>C

NM_001040143.2:c.4782G>C

NM_001371246.1:c.4782G>C

NM_001371247.1:c.4782G>C

NM_021007.3:c.4782G>C

Likely Pathogenic

PM6 PM5_Supporting PP3_Moderate PM2_Supporting PS1_Moderate PS4_Moderate

PM1 BS2 BS1 BP3 BP4 BP2 BA1 PS3 PS2 PP1

Evidence Links 0

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

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Epilepsy Sodium Channel VCEP

The c.4782G>C 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 (PS4, PM6)(PMID: 34004075, internal lab contributors). 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>T](PMID: 35365919, PMID: 23603762) is classified as likely pathogenic for complex neurodevelopmental disorder by the ClinGen Epilepsy Sodium Channel VCEP(PS1_Moderate). 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: PS4_Moderate, PM6, PS1_Moderate, PM2_Supporting, PP3_Moderate, PM5_Supporting. (version 1.0; November 26, 2024).

PM6

Observed in 2 de novo cases. 1. Observed at GeneDx one patient w/ infantile refractory seizures. De novo, but parentage not confirmed. PM6 +0.5 points 2. PMID: 34004075 reports 8month old F. Generalized tonic seizures developed at 1 day of age and spasms from 3 months of age. Diagnosed with Ohtahara syndrome at 3 months of age. WES revealed a de novo missense mutation in the SCN2A gene (c.4782G>C; p.Trp1594Cys). PM6 +0.5 Total +1 point = moderate

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.

PP3_Moderate

REVEL 0.924

PM2_Supporting

Absent in gnomAD v2 and v4

PS1_Moderate

SCN2A p.W1594C c.4782G>T occurs in the same gene with the same amino acid change, but has a different c. (G>T). This variant has been reported as de novo in 2 cases in the literature (PM6_Moderate), is absent in gnomAD v2 and v4 (PM2_Supporting), and has a REVEL score of 0.924 (PP3_Moderate). In sum, this variant is classified as a VLP 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.

PS4_Moderate

Observed in 1 case at ambry genetics. Female proband w/ congenital seizures (day 1 onset), global delay, unspecified dysmorphic features, and hypotonia. Family history unknown. Singleton case, no parental testing. Panel testing. PS4 +1 point = PS4_Moderate

PM1

Amino acid position not eligible for PM1 (using updating PM1 11/2024 alignment)

BS2