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: SCN1A vs undefined
  • Gene obtained from curated document aligns with the Allele Registry but not with ClinVar data
  • Despite there being a valid 'cspec' property in the messages there's a discrepancy in message contents and CSPEC data: * Message Gene: SCN1A CSPEC Genes: [ 'SCN1A' ] * Message MONDOs: MONDO:0000700 CSPEC MONDO: [ 'MONDO:0100135', 'MONDO:0018214', 'MONDO:0100062' ]
  • No CSPEC computed assertion could be determined for this classification!

Variant: NM_001165963.4(SCN1A):c.4465C>A (p.Gln1489Lys)

CA256608

12893 (ClinVar)

Gene: SCN1A
Condition: familial hemiplegic migraine
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: f21fc42b-a26b-42e5-87a4-93254a865e44
Approved on: 2024-10-01
Published on: 2025-08-28

HGVS expressions

NM_001165963.4:c.4465C>A
NM_001165963.4(SCN1A):c.4465C>A (p.Gln1489Lys)
NC_000002.12:g.165998049G>T
CM000664.2:g.165998049G>T
NC_000002.11:g.166854559G>T
CM000664.1:g.166854559G>T
NC_000002.10:g.166562805G>T
NG_011906.1:g.80591C>A
ENST00000689288.1:c.*2501C>A
ENST00000303395.9:c.4465C>A
ENST00000635750.1:c.4432C>A
ENST00000635776.1:c.4432C>A
ENST00000636194.1:c.*1958C>A
ENST00000637038.1:c.1327C>A
ENST00000637988.1:c.4432C>A
ENST00000640036.1:c.4432C>A
ENST00000641575.1:c.4429C>A
ENST00000641603.1:c.4183C>A
ENST00000641996.1:c.*4019C>A
ENST00000671940.1:c.*2408C>A
ENST00000673490.1:n.6938C>A
ENST00000674923.1:c.4465C>A
ENST00000303395.8:c.4465C>A
ENST00000375405.7:c.4432C>A
ENST00000409050.1:c.4381C>A
ENST00000423058.6:c.4465C>A
ENST00000473295.2:n.468C>A
NM_001165963.1:c.4465C>A
NM_001165964.1:c.4381C>A
NM_001202435.1:c.4465C>A
NM_006920.4:c.4432C>A
NR_110598.1:n.176-17564G>T
NM_001165963.2:c.4465C>A
NM_001165964.2:c.4381C>A
NM_001202435.2:c.4465C>A
NM_001353948.1:c.4465C>A
NM_001353949.1:c.4432C>A
NM_001353950.1:c.4432C>A
NM_001353951.1:c.4432C>A
NM_001353952.1:c.4432C>A
NM_001353954.1:c.4429C>A
NM_001353955.1:c.4429C>A
NM_001353957.1:c.4381C>A
NM_001353958.1:c.4381C>A
NM_001353960.1:c.4378C>A
NM_001353961.1:c.2023C>A
NM_006920.5:c.4432C>A
NR_148667.1:n.4901C>A
NM_001165963.3:c.4465C>A
NM_001165964.3:c.4381C>A
NM_001202435.3:c.4465C>A
NM_001353948.2:c.4465C>A
NM_001353949.2:c.4432C>A
NM_001353950.2:c.4432C>A
NM_001353951.2:c.4432C>A
NM_001353952.2:c.4432C>A
NM_001353954.2:c.4429C>A
NM_001353955.2:c.4429C>A
NM_001353957.2:c.4381C>A
NM_001353958.2:c.4381C>A
NM_001353960.2:c.4378C>A
NM_001353961.2:c.2023C>A
NM_006920.6:c.4432C>A
NR_148667.2:n.4882C>A
More

Pathogenic

Met criteria codes 5
PM2_Supporting PS3 PM1 PP3_Moderate PP1_Strong
Not Met criteria codes 9
PVS1 BA1 BS2 BS3 BS4 BS1 BP4 PM3 PM4

Evidence Links 2

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 c.4465C>A variant in SCN1A is a missense variant predicted to cause substitution of glutamine by lysine at amino acid 1489 (p.Gln1489Lys). This variant has been reported to segregate with hemiplegic migraine in 18 affected individuals from 3 families (PMID: 16054936) (PP1_strong). This variant is absent from gnomAD (v4) (PM2_supporting). Whole-cell voltage-clamp studies were performed on human tsA201 cell model that showed increased persistent current but also enhanced entry into slow activation as well as delayed recovery from fast and slow inactivation indicating that this variant impacts protein function (PMIDs: 18621678, 18632931) (PS3). This variant resides within a Pathogenic Enriched Region that is defined as a mutational hotspot by the ClinGen Epilepsy Sodium Channel VCEP (PM1). The computational predictor (REVEL) gives a score of 0.936, evidence that correlates with impact to SCN1A function (PP3_moderate). In summary, this variant meets the criteria to be classified as pathogenic for autosomal dominant hemiplegic migraine based on ACMG/AMP criteria applied, as specified by the ClinGen Epilepsy Sodium Channel VCEP: PP1_strong, PS3, PP3_moderate, PM1, PM2_supporting (v1.0; approved September 24, 2024).
Met criteria codes
PM2_Supporting
absent in controls (gnomAD v4)
PS3
Whole-cell voltage-clamp studies were performed on human tsA201 cell model. Showed mutation has effects on the gating properties of the channel that can be consistent with both hyper- and hypoexcitability. PubMed:18632931
Whole-cell voltage-clamp studies were performed on human tsA201 cell model. Compared to WT-NaV1.1, Q1489K exhibited increased persistent current but also enhanced entry into slow inactivation as well as delayed recovery from fast and slow inactivation, thus resulting in a predominantly loss-of-function phenotype further demonstrated by a greater loss of channel availability during repetitive stimulation. (Persistent current increased by greater than 135% compared to wild-type) PubMed:18621678
PM1
Variant is located within a Pathogenic Enriched Region (PER).
PP3_Moderate
REVEL score = 0.936 (Pathogenic Moderate)
PP1_Strong
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
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
BS2
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
BS4
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
BP4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
Curation History
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