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]

Link to SEPIO compliant JSON-LD document

Variant: NM_001330260.2(SCN8A):c.4687A>G (p.Ile1563Val)

CA6571849

568706 (ClinVar)

Gene: SCN8A

Condition: complex neurodevelopmental disorder

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 36b5f1d9-3040-4b3a-8eda-e4d23c4da206

Approved on: 2024-05-09

Published on: 2024-05-09

HGVS expressions

NM_001330260.2:c.4687A>G

NM_001330260.2(SCN8A):c.4687A>G (p.Ile1563Val)

NC_000012.12:g.51794533A>G

CM000674.2:g.51794533A>G

NC_000012.11:g.52188317A>G

CM000674.1:g.52188317A>G

NC_000012.10:g.50474584A>G

NG_021180.2:g.208298A>G

NG_021180.3:g.209576A>G

ENST00000354534.11:c.4687A>G

ENST00000627620.5:c.4687A>G

ENST00000636945.2:c.2751A>G

ENST00000662684.1:c.4687A>G

ENST00000668547.1:c.4564A>G

ENST00000354534.10:c.4687A>G

ENST00000355133.7:c.4564A>G

ENST00000545061.5:c.4564A>G

ENST00000599343.5:c.4720A>G

ENST00000627620.2:c.4687A>G

NM_001177984.2:c.4564A>G

NM_014191.3:c.4687A>G

NM_001330260.1:c.4687A>G

NM_001369788.1:c.4564A>G

NM_014191.4:c.4687A>G

NM_001177984.3:c.4564A>G

Benign

BS1 BS2

PS2 PS4 PP3 PM6 BP4

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 1.0.0

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Epilepsy Sodium Channel VCEP

The c.4687A>G variant in SCN8A is a missense variant predicted to cause the substitution of isoleucine by valine at amino acid 1563 (p.Ile1563Val). The variant is present at a frequency of 0.000008674 (14 alleles) of the total population in gnomAD v4.0, which exceeds the threshold for BS1. Additionally, the variant was identified in 7 unaffected adults who were referred for clinical testing as part as trio exome analysis (internal data, GeneDx, July 2023). It was identified as homozygous in an individual undergoing trio exome sequencing for an unrelated condition, without a neurodevelopmental disorder, in which both parents were heterozygous and unaffected (BS2, GeneDx internal data, July 2023). In summary, this variant meets the criteria for BENIGN for Autosomal Dominant Complex Neurodevelopmental Disorder based on the ACMG/AMP criteria applied, as specified by the ClinGen Epilepsy Sodium Channel VCEP (Version 1.0, approved 7/25/23): BS1, BS2

BS1

0.000008674 of total population, 14 alleles (gnomAD v4.0)

BS2

This variant was identified in 7 unaffected adults who were referred for clinical testing as part as exome trio analysis. Variant observed in a homozygous state in a teenager undergoing exome sequencing for an unrelated clinical indication who had no reported history of neurodevelopmental features in which both parents heterozygous and unaffected (GeneDx internal data, July 2023).

PS2

No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

PS4

No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

PP3

REVEL=0.426

PM6

No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

BP4

REVEL=0.426

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