Variant: NM_001040142.2(SCN2A):c.2657T>C (p.Leu886Ser)

CA317886

206972 (ClinVar)

Gene: SCN2A

Condition: complex neurodevelopmental disorder

Inheritance Mode: Autosomal dominant inheritance

UUID: 7e708ed4-b2fc-4bf7-8cf3-3c83e2b68ad7

Approved on: 2025-03-25

Published on: 2025-04-24

HGVS expressions

NM_001040142.2:c.2657T>C
NM_001040142.2(SCN2A):c.2657T>C (p.Leu886Ser)
NC_000002.12:g.165344649T>C
CM000664.2:g.165344649T>C
NC_000002.11:g.166201159T>C
CM000664.1:g.166201159T>C
NC_000002.10:g.165909405T>C
NG_008143.1:g.110248T>C
ENST00000631182.3:c.2657T>C
ENST00000375437.7:c.2657T>C
ENST00000636071.2:c.2657T>C
ENST00000636135.1:c.*976T>C
ENST00000636384.2:c.*644T>C
ENST00000636662.2:c.*3180T>C
ENST00000636769.1:c.*599T>C
ENST00000636985.2:c.2261T>C
ENST00000637266.2:c.2657T>C
ENST00000673831.1:c.95T>C
ENST00000673883.1:c.95T>C
ENST00000674133.1:c.508T>C
ENST00000283256.10:c.2657T>C
ENST00000375427.4:c.2657T>C
ENST00000375437.6:c.2657T>C
ENST00000480032.4:n.2800T>C
ENST00000631182.2:c.2657T>C
NM_001040142.1:c.2657T>C
NM_001040143.1:c.2657T>C
NM_021007.2:c.2657T>C
NM_001040143.2:c.2657T>C
NM_001371246.1:c.2657T>C
NM_001371247.1:c.2657T>C
NM_021007.3:c.2657T>C

Likely Pathogenic

• Met criteria codes: PM2_Supporting PP3_Moderate PM1 PM6 PS4_Supporting

• Not Met criteria codes: BA1 BS2 BS4 BS3 BS1 BP4 BP1 BP3 BP2 BP7 BP5 PVS1 PS3 PS2 PS1 PP4 PP1 PP2 PM5 PM4 PM3

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 2.0.0

Evidence submitted by expert panel

Epilepsy Sodium Channel VCEP

The c.2657T>C variant in SCN2A is a missense variant predicted to cause a substitution of leucine by serine at amino acid 886 (p.Leu886Ser). This variant has been identified as a de novo occurrence with unconfirmed parental relationships in 2 individuals with a complex neurodevelopmental disorder (PM6); (PMID: 3541799; internal data GeneDx). It has also been identified in an additional proband with a complex neurodevelopmental disorder (PS4_supporting) (internal data, Labcorp). This variant is absent from gnomAD v4.0) (PM2_supporting). The computational predictor REVEL gives a score of 0.971, evidence that correlates with impact to SCN2A function (PP3_moderate). This variant resides within a region of SCN2A that is defined as a mutation hotspot by the ClinGen Epilepsy Sodium Channel VCEP (PM1). 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: (PP3_moderate, PM1, PM6, PM2_supporting, PS4_supporting). Approved March 25, 2025.

Met criteria codes

• PM2_Supporting: Absent in controls (gnomAD v:4.0)
• PP3_Moderate: REVEL score = 0.971
• PM1: Located in PER 6
• PM6: Reported de novo in one case w/ neonatal epilepsy (PMID: 35431799) (0.5 pts). Identified in the de novo state in a patient with epilepsy by a clinical lab (GeneDx) (0.5 pts). Reported de novo in one case in broad NICU cohort (PMID: 38778310) (0 pts).
• PS4_Supporting: Reported by one lab (LabCorp/Invitae) in a person with a neurodevelopmental disorder.

Not Met criteria codes

• BA1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BS2: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BS4: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BS3: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BS1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BP4: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BP1: N/A
• BP3: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BP2: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BP7: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BP5: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PVS1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PS3: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PS2: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PS1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PP4: N/A
• PP1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PP2: N/A
• PM5: There are novel missense changes reported in SCN2A and paralogous genes, but since only one is classified as P/LP, does not meet threshold to apply PM5. SCN1A:p.Leu895Pro (ClinVar ID: 1367610) was classified as pathogenic in ClinVar by a clinical lab (Invitae); SCN3A:p.Leu887Phe (ClinVar ID: 1989062) was classified as a VUS by a clinical lab (Invitae); SCN2A:p.Leu886Met was classified as a VUS by a clinical lab (Invitae); SCN2A:p.Leu886Val (ClinVar ID: 2065720) was classified as a VUS by a clinical lab (Invitae)
• PM4: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PM3: N/A