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 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_001165963.4(SCN1A):c.3629C>T (p.Thr1210Met)

CA1942910

658067 (ClinVar)

Gene: SCN1A
Condition: generalized epilepsy with febrile seizures plus
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: 9c043e12-73f5-45a6-9512-93c1204b1be0
Approved on: 2024-04-30
Published on: 2024-11-05

HGVS expressions

NM_001165963.4:c.3629C>T
NM_001165963.4(SCN1A):c.3629C>T (p.Thr1210Met)
NC_000002.12:g.166013820G>A
CM000664.2:g.166013820G>A
NC_000002.11:g.166870330G>A
CM000664.1:g.166870330G>A
NC_000002.10:g.166578576G>A
NG_011906.1:g.64820C>T
ENST00000689288.1:c.*1665C>T
ENST00000303395.9:c.3629C>T
ENST00000635750.1:c.3596C>T
ENST00000635776.1:c.3596C>T
ENST00000636194.1:c.*1122C>T
ENST00000637038.1:c.427C>T
ENST00000637968.1:n.3881C>T
ENST00000637988.1:c.3596C>T
ENST00000640036.1:c.3596C>T
ENST00000641575.1:c.3593C>T
ENST00000641603.1:c.3629C>T
ENST00000641996.1:c.*3183C>T
ENST00000671940.1:c.*1572C>T
ENST00000673490.1:n.6102C>T
ENST00000674923.1:c.3629C>T
ENST00000303395.8:c.3629C>T
ENST00000375405.7:c.3596C>T
ENST00000409050.1:c.3545C>T
ENST00000423058.6:c.3629C>T
NM_001165963.1:c.3629C>T
NM_001165964.1:c.3545C>T
NM_001202435.1:c.3629C>T
NM_006920.4:c.3596C>T
NR_110598.1:n.176-1793G>A
NM_001165963.2:c.3629C>T
NM_001165964.2:c.3545C>T
NM_001202435.2:c.3629C>T
NM_001353948.1:c.3629C>T
NM_001353949.1:c.3596C>T
NM_001353950.1:c.3596C>T
NM_001353951.1:c.3596C>T
NM_001353952.1:c.3596C>T
NM_001353954.1:c.3593C>T
NM_001353955.1:c.3593C>T
NM_001353957.1:c.3545C>T
NM_001353958.1:c.3545C>T
NM_001353960.1:c.3542C>T
NM_001353961.1:c.1187C>T
NM_006920.5:c.3596C>T
NR_148667.1:n.4001C>T
NM_001165963.3:c.3629C>T
NM_001165964.3:c.3545C>T
NM_001202435.3:c.3629C>T
NM_001353948.2:c.3629C>T
NM_001353949.2:c.3596C>T
NM_001353950.2:c.3596C>T
NM_001353951.2:c.3596C>T
NM_001353952.2:c.3596C>T
NM_001353954.2:c.3593C>T
NM_001353955.2:c.3593C>T
NM_001353957.2:c.3545C>T
NM_001353958.2:c.3545C>T
NM_001353960.2:c.3542C>T
NM_001353961.2:c.1187C>T
NM_006920.6:c.3596C>T
NR_148667.2:n.3982C>T
More

Likely Pathogenic

Met criteria codes 3
PM5_Supporting PP3_Moderate PS4
Not Met criteria codes 4
BS2 BS1 PVS1 PS1

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 SCN1A Version 1.0.0

Criteria Specification Approval History
Criteria Specifications for this VCEP
Evidence submitted by expert panel
Epilepsy Sodium Channel VCEP
The NM_001165963.4(SCN1A):c.3629C>T is a missense variant predicted to cause substitution of threonine by methionine at amino acid 1210 (p.Thr1210Met). The variant has been identified in two probands with consistent phenotypes (Genetic epilepsy with febrile seizures plus) in published literature (PMID:35074891 and PMID:28202706)(PS4). One proband inherited the variant from an unaffected father (PMID:28202706). Another missense variant at the same amino acid position in SCN1A (c.3629C>A, p.Thr1210Lys) has been classified as likely pathogenic for a consistent phenotype (Dravet syndrome)(PM5_supporting). The allele frequency for the variant is 0.002% with 4 alleles in gnomAD V2.1.1 (PM2_supporting and BS1 are not met). The computational predictor REVEL gives a score of 0.841, which is above the threshold of 0.773, evidence that correlates with a maximum strength of PP3_Moderate. In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal dominant Genetic epilepsy with febrile seizures plus on the ACMG/AMP criteria applied, as specified by the ClinGen Epilepsy Sodium Channel VCEP: PS4, PM5_supporting, PP3_Moderate. (version 1.0; March 26, 2024)
Met criteria codes
PM5_Supporting
Missense at same amino acid position in same gene is Likely Pathogenic using VCEP criteria (c.3629C>A, p.T1210K) (PM2_Supporting, PP3_moderate, PS2_Strong). PM5_supporting based on current de novo weights. To get to PM5_Moderate, de novo points would have to be adjusted so that a proband with Dravet and confirmed de novo could get to PS2_Very Strong. Otherwise, this will stay as PM5_Supporting.
PP3_Moderate
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS4
PMID: 35074891 proband with GEFS+ (PS4 +1). Used as evidence towards classification. PMID: 28202706 proband with febrile seizures (possibly GEFS+ based on supplement table) has variant and was inherited from unaffected father PS4 +1. Paternal half sister is also affected, but genetic testing was not performed. Not used as evidence towards classification.
Not Met criteria codes
BS2
PMID: 28202706 father of proband with GEFS+ is unaffected. Reviewed at meeting and decided that mild phenotypes may not be fully penetrant. Therefore, not met.
BS1
The allele frequency for the variant is 0.002% with 4 alleles in gnomAD V2.1.1. Allele frequency is above threshold of 0.0004%, but allele count threshold of 5 is not met . Therefore PM2 and BS1 are not met.
PVS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS1
Amino acid changes in paralogous genes are all VUS or VLB in ClinVar
Curation History
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