Evidence Repository
The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]
  • Gene label mismatch: SCN2A vs undefined
  • Gene obtained from curated document aligns with the Allele Registry but not with ClinVar data
  • No CSPEC computed assertion could be determined for this classification!

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

CA317886

206972 (ClinVar)

Gene: SCN2A
Condition: complex neurodevelopmental disorder
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
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
More

Likely Pathogenic

Met criteria codes 5
PM6 PM1 PS4_Supporting PM2_Supporting PP3_Moderate
Not Met criteria codes 21
PVS1 BA1 PM5 PM4 PM3 BS2 BS4 BS3 BS1 BP7 BP5 BP4 BP1 BP3 BP2 PS3 PS2 PS1 PP4 PP1 PP2

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 2.0.0

Criteria Specification Approval History
Criteria Specifications for this VCEP
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
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).
PM1
Located in PER 6
PS4_Supporting
Reported by one lab (LabCorp/Invitae) in a person with a neurodevelopmental disorder.
PM2_Supporting
Absent in controls (gnomAD v:4.0)
PP3_Moderate
REVEL score = 0.971
Not Met criteria codes
PVS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BA1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
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
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
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
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
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
Curation History
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