Evidence Repository - Clinical Genome Resources

The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]

Variant: NM_001330260.2(SCN8A):c.2533T>C (p.Ser845Pro)

CA16042904

373333 (ClinVar)

Gene: SCN8A (HGNC:6334)

Condition: complex neurodevelopmental disorder (MONDO:0100038)

Inheritance Mode: Autosomal dominant inheritance

UUID: 384cff6d-77c4-4955-84eb-ed960c74d6dc

Approved on: 2025-08-26

Published on: 2025-12-17

HGVS expressions

NM_001330260.2:c.2533T>C

NM_001330260.2(SCN8A):c.2533T>C (p.Ser845Pro)

NC_000012.12:g.51762665T>C

CM000674.2:g.51762665T>C

NC_000012.11:g.52156449T>C

CM000674.1:g.52156449T>C

NC_000012.10:g.50442716T>C

NG_021180.2:g.176430T>C

NG_021180.3:g.177708T>C

ENST00000354534.11:c.2533T>C

ENST00000548086.3:c.380T>C

ENST00000627620.5:c.2533T>C

ENST00000636945.2:c.537T>C

ENST00000662684.1:c.2533T>C

ENST00000668547.1:c.2533T>C

ENST00000354534.10:c.2533T>C

ENST00000355133.7:c.2533T>C

ENST00000545061.5:c.2533T>C

ENST00000550891.4:n.2661T>C

ENST00000599343.5:c.2566T>C

ENST00000627620.2:c.2533T>C

NM_001177984.2:c.2533T>C

NM_014191.3:c.2533T>C

NM_001330260.1:c.2533T>C

NM_001369788.1:c.2533T>C

NM_014191.4:c.2533T>C

NM_001177984.3:c.2533T>C

Likely Pathogenic

PM1 PP3_Moderate PM2_Supporting PM5_Supporting

PS4 PS2 PS3 PS1 BA1 PP1 PM4 PM6 BS3 BS1 BS2 BP5 BP7 BP2 BP3 BP4 PVS1

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 SCN8A Version 2.0.0

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Epilepsy Sodium Channel VCEP

The NM_001330260.2:c.2533T>C variant in SCN8A is a missense variant predicted to cause substitution of serine by proline at amino acid 845 (p.Ser845Pro). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). The computational predictor REVEL gives a score of 0.960, which is above the threshold of 0.773, evidence that correlates with impact to SCN8A function (PP3_Moderate). Another missense variant (c.2534C>T (p.Ser845Phe), ClinVar Variation ID: 207109) in the same codon has been classified as likely pathogenic for autosomal dominant complex neurodevelopmental disorder by the ClinGen Epilepsy Sodium Channel VCEP (PM5_Supporting). This variant resides within a region, amino acids 844-852, of SCN8A that is defined as a mutational hotspot and/or critical functional domain 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: PM1, PP3_Moderate, PM2_Supporting, PM5_Supporting. (VCEP specifications version 2.0.0; approved 8/26/25).

PM1

This variant resides within a region, amino acids 844-852, of SCN8A that is defined as a mutational hotspot and/or critical functional domain by the ClinGen Epilepsy Sodium Channel VCEP (PM1).

PP3_Moderate

The computational predictor REVEL gives a score of 0.960, which is above the threshold of 0.773, evidence that correlates with impact to SCN8A function (PP3_Moderate).

PM2_Supporting

This variant is absent from gnomAD v4.1.0 (PM2_Supporting).

PM5_Supporting

Another missense variant (c.2534C>T (p.Ser845Phe), ClinVar Variation ID: 207109) in the same codon has been classified as likely pathogenic for autosomal dominant complex neurodevelopmental disorder by the ClinGen Epilepsy Sodium Channel VCEP (PM5_Supporting).

PS4