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 obtained from curated document aligns with the Allele Registry but not with ClinVar data
  • No CSPEC computer assertion could be determined for this classification!


Variant: NM_001330260.2(SCN8A):c.3953A>G (p.Asn1318Ser)

CA384904367

694309 (ClinVar)

Gene: SCN8A
Condition: complex neurodevelopmental disorder
Inheritance Mode: Autosomal dominant inheritance
UUID: 3d72f96d-dfa8-4992-81f0-bf6b4b511a81
Approved on: 2024-05-09
Published on: 2024-05-09

HGVS expressions

NM_001330260.2:c.3953A>G
NM_001330260.2(SCN8A):c.3953A>G (p.Asn1318Ser)
NC_000012.12:g.51786552A>G
CM000674.2:g.51786552A>G
NC_000012.11:g.52180336A>G
CM000674.1:g.52180336A>G
NC_000012.10:g.50466603A>G
NG_021180.2:g.200317A>G
NG_021180.3:g.201595A>G
ENST00000354534.11:c.3953A>G
ENST00000548086.3:c.1747A>G
ENST00000627620.5:c.3953A>G
ENST00000636945.2:c.2017A>G
ENST00000662684.1:c.3953A>G
ENST00000668547.1:c.3830A>G
ENST00000354534.10:c.3953A>G
ENST00000355133.7:c.3830A>G
ENST00000545061.5:c.3830A>G
ENST00000548086.1:n.204A>G
ENST00000599343.5:c.3986A>G
ENST00000627620.2:c.3953A>G
NM_001177984.2:c.3830A>G
NM_014191.3:c.3953A>G
NM_001330260.1:c.3953A>G
NM_001369788.1:c.3830A>G
NM_014191.4:c.3953A>G
NM_001177984.3:c.3830A>G
More

Likely Pathogenic

Met criteria codes 4
PM6_Supporting PS2 PP3_Moderate PM2_Supporting
Not Met criteria codes 2
PM1 PM5

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 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.3953A>G variant in SCN8A is a missense variant predicted to cause substitution of asparagine by serine at amino acid 1318 (p.Asn1318Ser). This variant has been reported as de novo with confirmed parental relationships in 2 individuals (PMID: 30968951, 31672125) and de novo with unconfirmed parental relationships in 1 individual (PMID: 35230384) with consistent phenotypes (PS2, PM6_Supporting). A novel missense variant at the same position in the paralogous gene, SCN1A (p.Asn1338Thr) has been reported as pathogenic, however, two novel missense variants are required to meet PM5_Supporting so this criterion was not applied. This variant is absent from the population database, gnomAD v2.1.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.832, which is above the threshold of 0.773, evidence that correlates with a strength of PP3_Moderate. 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: PS2, PM6_Supporting, PM2_Supporting, PP3_Moderate (version 1.0; approved 5/23/23).
Met criteria codes
PM6_Supporting
The variant was identified de novo in a proband with neurodevelopmental disorder with Chinese ancestry (PMID: 35230384).
PS2
This variant was identified in PMID: 30968951. The variant was ascertained via gene panel; de novo with maternity and paternity confirmed (PS2 applied in paper) in proband with ataxia and epilepsy. The variant was identified via trio exome sequencing which identified de novo variant in female proband of Chinese ancestry with early infantile epileptic encephalopathy (PMID: 31672125).
PP3_Moderate
REVEL=0.832
PM2_Supporting
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
Not Met criteria codes
PM1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM5
novel missense variant in paralogous gene, SCN1A p.Asn1338Thr - PMID: 24901346, 25356970, 26795593. However, two novel missense variants in paralogous gene are required to meet PM5_Supporting.
Curation History
The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. If you have questions about the information contained on this website, please see a health care professional.
¤ Powered by BCM's Genboree.