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.1709G>A (p.Ser570Asn)

CA16043652

374331 (ClinVar)

Gene: SCN1A
Condition: generalized epilepsy with febrile seizures plus
Inheritance Mode: Autosomal dominant inheritance
UUID: 108d2b71-c61b-47e5-aaf4-b6d948c9c272
Approved on: 2024-07-30
Published on: 2024-11-05

HGVS expressions

NM_001165963.4:c.1709G>A
NM_001165963.4(SCN1A):c.1709G>A (p.Ser570Asn)
NC_000002.12:g.166044003C>T
CM000664.2:g.166044003C>T
NC_000002.11:g.166900513C>T
CM000664.1:g.166900513C>T
NC_000002.10:g.166608759C>T
NG_011906.1:g.34637G>A
ENST00000689288.1:c.1709G>A
ENST00000303395.9:c.1709G>A
ENST00000635750.1:c.1709G>A
ENST00000635776.1:c.1709G>A
ENST00000636194.1:c.1709G>A
ENST00000636759.1:c.*1499G>A
ENST00000637968.1:n.1961G>A
ENST00000637988.1:c.1709G>A
ENST00000640036.1:c.1709G>A
ENST00000641575.1:c.1706G>A
ENST00000641603.1:c.1709G>A
ENST00000641996.1:c.*1263G>A
ENST00000671940.1:c.1709G>A
ENST00000673490.1:n.4182G>A
ENST00000674923.1:c.1709G>A
ENST00000303395.8:c.1709G>A
ENST00000375405.7:c.1709G>A
ENST00000409050.1:c.1709G>A
ENST00000423058.6:c.1709G>A
NM_001165963.1:c.1709G>A
NM_001165964.1:c.1709G>A
NM_001202435.1:c.1709G>A
NM_006920.4:c.1709G>A
NM_001165963.2:c.1709G>A
NM_001165964.2:c.1709G>A
NM_001202435.2:c.1709G>A
NM_001353948.1:c.1709G>A
NM_001353949.1:c.1709G>A
NM_001353950.1:c.1709G>A
NM_001353951.1:c.1709G>A
NM_001353952.1:c.1709G>A
NM_001353954.1:c.1706G>A
NM_001353955.1:c.1706G>A
NM_001353957.1:c.1709G>A
NM_001353958.1:c.1709G>A
NM_001353960.1:c.1706G>A
NM_001353961.1:c.-717G>A
NM_006920.5:c.1709G>A
NR_148667.1:n.2114G>A
NM_001165963.3:c.1709G>A
NM_001165964.3:c.1709G>A
NM_001202435.3:c.1709G>A
NM_001353948.2:c.1709G>A
NM_001353949.2:c.1709G>A
NM_001353950.2:c.1709G>A
NM_001353951.2:c.1709G>A
NM_001353952.2:c.1709G>A
NM_001353954.2:c.1706G>A
NM_001353955.2:c.1706G>A
NM_001353957.2:c.1709G>A
NM_001353958.2:c.1709G>A
NM_001353960.2:c.1706G>A
NM_001353961.2:c.-717G>A
NM_006920.6:c.1709G>A
NR_148667.2:n.2095G>A
More

Likely Pathogenic

Met criteria codes 4
PM2_Supporting PS4 PP3_Moderate PM5_Supporting
Not Met criteria codes 2
PS1 PM1

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 c.1709G>A variant in SCN1A is a missense variant predicted to cause substitution of serine by asparagine at amino acid 570 (p.Ser570Asp). The variant has been identified in multiple unrelated individuals meeting criteria for generalized epilepsy with febrile seizures plus or an unspecified epilepsy condition (PS4)(internal lab contributors). This variant was observed in one unaffected parent (internal lab contributors). It is absent from the population database gnomAD v2.1.1 and v4.1.0 (PM2_Supporting). The computational predictor REVEL gives a score of 0.852, which is above the threshold of 0.773, evidence that correlates with a maximum strength of PP3_Moderate. Additionally, another missense variant in the same codon c.1709G>T, p.S570I in the same codon reaches likely pathogenic based on current criteria (PM5_Supporting). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal dominant generalized epilepsy with febrile seizures plus based on the ACMG/AMP criteria applied, as specified by the ClinGen Epilepsy Sodium Channel VCEP: PS4, PM2_Supporting, PP3_Moderate, PM5_Supporting. (version 1.0; March 26, 2024).
Met criteria codes
PM2_Supporting
Absent in gnomAD v2.1.1 and v4.1.0
PS4
5 unrelated individuals meet GEFS+ were shared from Invitae. All probands have febrile seizures and generalized seizures. Two of the five probands also have developmental delay and/or intellectual disability. However, of the unrelated families, 1 parent is an unaffected het carrier and therefore not counting this proband towards classification to be conservative (4 points) 1 individual with other epilepsy type were shared from Ambry (0.5 points) Total = 4.5 points (PS4_Met) One 3yo proband w/ WES testing no clinical information provided and has second variant in PDHA1 (XL/LOF) that is NMD-prone. Posey et al 2017 (PMID: 27959697). Not used towards variant classification.
PP3_Moderate
REVEL 0.852 > 0.773 threshold
PM5_Supporting
p.S570I, c.1709G>T (PS4, PP3_Moderate, PM2_Supporting = VLP) p.S570C, c.1708A>T (PP3_Moderate, PM2_Supporting = VUS) No variants in paralogous genes
Not Met criteria codes
PS1
No variants in paralogous genes
PM1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
Curation History
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