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Variant: NM_021007.3:c.4780T>A

CA349036828

Gene: SCN2A
Condition: complex neurodevelopmental disorder
Inheritance Mode: Autosomal dominant inheritance
UUID: b4c02e79-b083-43e2-ac2a-db2bb1fb5f50
Approved on: 2024-11-26
Published on: 2025-02-20

HGVS expressions

NM_021007.3:c.4780T>A
NC_000002.12:g.165386974T>A
CM000664.2:g.165386974T>A
NC_000002.11:g.166243484T>A
CM000664.1:g.166243484T>A
NC_000002.10:g.165951730T>A
NG_008143.1:g.152573T>A
ENST00000631182.3:c.4780T>A
ENST00000375437.7:c.4780T>A
ENST00000636071.2:c.4780T>A
ENST00000636135.1:c.*3099T>A
ENST00000636384.2:c.*2767T>A
ENST00000636662.2:c.*5303T>A
ENST00000636769.1:c.*2722T>A
ENST00000636985.2:c.4384T>A
ENST00000637266.2:c.4780T>A
ENST00000283256.10:c.4780T>A
ENST00000375427.4:c.4780T>A
ENST00000375437.6:c.4780T>A
ENST00000480032.4:n.8211T>A
ENST00000631182.2:c.4780T>A
NM_001040142.1:c.4780T>A
NM_001040143.1:c.4780T>A
NM_021007.2:c.4780T>A
NM_001040142.2:c.4780T>A
NM_001040143.2:c.4780T>A
NM_001371246.1:c.4780T>A
NM_001371247.1:c.4780T>A
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Likely Pathogenic

Met criteria codes 4
PM6 PM2 PP3_Moderate PS2_Moderate

Evidence Links 0

Expert Panel

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.4780T>A variant in SCN2A is a missense variant predicted to cause substitution of tryptophan by cysteine at amino acid 1594 (p.Trp1594Arg). The variant has been identified in multiple individuals meeting criteria for complex neurodevelopmental disorder (PM6)(PMID: 34004075, 28256214, 28135719, 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 0.968, which is above the threshold of 0.773, evidence that correlates with a maximum strength of PP3_Moderate. Additionally, two other missense variants in the same codon c.4782G>C, p.Trp1594Cys and c.4782G>T, p.Trp1594Cys also reach 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
PM6
Reported in 3 de novo cases. PM6 +1 point = moderate 1. GeneDx - seen de novo (assumed) in one patient in Epilepsy panel test and reported as LPATH. Parentage not confirmed. PM6 +0.5 points 2. Morichi et al (PMID: 34004075): Hypotonia and respiratory disturbance developed immediately after birth, with systemic tonic seizures at 8 days of age. EEG showed high-voltage slow waves. Hypoxic-ischemic encephalopathy was diagnosed on brain magnetic resonance imaging at 1 year of age. WES revealed a de novo missense mutation in the SCN2A. PM6 +0.5 3. Ben-Shalom et al 2017 (PMID: 28256214): Male. No age. Developmental delay. De novo. Parentage not confirmed. No seizure phenotype. Not assigning points for developmental delay. PM6 no points.
PM2
Absent in gnomAD v2 and v4
PP3_Moderate
REVEL 0.968
PS2_Moderate
Reported in Decipher database (PMID: 28135719). Patient details are not in supplemental table but they are in Decipher database(ID 261030). De novo with parentage confirmed. Bilateral tonic-clonic seizure; Cerebral atrophy; Eruption failure; Generalized myoclonic seizure; Infantile encephalopathy; Intellectual disability, profound; Optic atrophy; Progressive microcephaly; Spasticity. PS2 +1 points
Curation History
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