Variant: NM_001165963.4(SCN1A):c.83G>A (p.Arg28His)

CA221620

93664 (ClinVar)

Gene: SCN1A

Condition: generalized epilepsy with febrile seizures plus

Inheritance Mode: Autosomal dominant inheritance

UUID: 355c8f59-20c9-4b0f-b5d5-dea5411c41ec

Approved on: 2024-09-03

Published on: 2024-11-05

HGVS expressions

NM_001165963.4:c.83G>A
NM_001165963.4(SCN1A):c.83G>A (p.Arg28His)
NC_000002.12:g.166073539C>T
CM000664.2:g.166073539C>T
NC_000002.11:g.166930049C>T
CM000664.1:g.166930049C>T
NC_000002.10:g.166638295C>T
NG_011906.1:g.5101G>A
ENST00000689288.1:c.83G>A
ENST00000303395.9:c.83G>A
ENST00000635750.1:c.83G>A
ENST00000635776.1:c.83G>A
ENST00000636194.1:c.83G>A
ENST00000636759.1:c.83G>A
ENST00000637968.1:n.335G>A
ENST00000637988.1:c.83G>A
ENST00000640036.1:c.83G>A
ENST00000641575.1:c.83G>A
ENST00000641603.1:c.83G>A
ENST00000641996.1:c.83G>A
ENST00000642141.1:n.476G>A
ENST00000671940.1:c.83G>A
ENST00000673490.1:n.377G>A
ENST00000674923.1:c.83G>A
ENST00000303395.8:c.83G>A
ENST00000375405.7:c.83G>A
ENST00000409050.1:c.83G>A
ENST00000423058.6:c.83G>A
ENST00000507401.2:n.474G>A
NM_001165963.1:c.83G>A
NM_001165964.1:c.83G>A
NM_001202435.1:c.83G>A
NM_006920.4:c.83G>A
NM_001165963.2:c.83G>A
NM_001165964.2:c.83G>A
NM_001202435.2:c.83G>A
NM_001353948.1:c.83G>A
NM_001353949.1:c.83G>A
NM_001353950.1:c.83G>A
NM_001353951.1:c.83G>A
NM_001353952.1:c.83G>A
NM_001353954.1:c.83G>A
NM_001353955.1:c.83G>A
NM_001353957.1:c.83G>A
NM_001353958.1:c.83G>A
NM_001353960.1:c.83G>A
NM_001353961.1:c.-2343G>A
NM_006920.5:c.83G>A
NR_148667.1:n.488G>A
NM_001165963.3:c.83G>A
NM_001165964.3:c.83G>A
NM_001202435.3:c.83G>A
NM_001353948.2:c.83G>A
NM_001353949.2:c.83G>A
NM_001353950.2:c.83G>A
NM_001353951.2:c.83G>A
NM_001353952.2:c.83G>A
NM_001353954.2:c.83G>A
NM_001353955.2:c.83G>A
NM_001353957.2:c.83G>A
NM_001353958.2:c.83G>A
NM_001353960.2:c.83G>A
NM_001353961.2:c.-2343G>A
NM_006920.6:c.83G>A
NR_148667.2:n.469G>A

Likely Benign

• Met criteria codes: PP3_Moderate BS1

• Not Met criteria codes: PS1 PS2 PS4 BA1 PM5 PM1 PM6 PM2

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 SCN1A Version 1.0.0

Evidence submitted by expert panel

Epilepsy Sodium Channel VCEP

The c.83G>A variant in SCN1A is a missense variant predicted to cause substitution of arginine by histidine at amino acid 28 (p.Arg28His). The variant has been identified in 4 individuals with seizures with variable ages of onset, inconsistent segregation patterns and/or in the presence of variants in other epilepsy-associated genes (PMID:36801247; internal data, Invitae. PS4_not met). A novel missense variant at the same position in SCN1A (p.R28C) has been previously reported, in addition to missense variants at the corresponding position in a paralogous gene (SCN2A: p.R28C & p.R28H), however, none of these variants met PLP classification per these criteria (PS1_not met; PM5_not met). The variant is present at a relatively high frequency (0.0006%, 7 alleles) in non-Finnish European population in gnomAD v4.1 (BS1). It was also identified in multiple individuals referred for testing for non-neurological indications for which an alternative genetic diagnosis was identified (internal data, GeneDx). The computational predictor REVEL gives a score of 0.83, 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 Benign for autosomal dominant SCN1A-related disorder, based on the ACMG/AMP criteria applied, as specified by the ClinGen Epilepsy Sodium Channel VCEP: BS1, PP3_Moderate (version 1.0, approved August 27, 2024).

Met criteria codes

• PP3_Moderate: REVEL=0.83
• BS1: This variant is present at a MAF of 0.0006% (7 alleles) in non-Finnish European population, gnomAD v4.1, which exceeds the threshold of 0.0004%.

Not Met criteria codes

• PS1: Identical aa substitution in SCN2A (p.R28H) has been reported in an individual with seizures and delayed speech & language development, no parental segregation data available. Does not meet PLP per these criteria.
• PS2: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PS4: The variant has been identified in several individuals with seizures with variable ages of onset, inconsistent segregation patterns and/or in the presence of variants in other epilepsy-associated genes
• BA1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PM5: Novel amino acid substitution in SCN1A (p.R28C) and non-identical aa substitution in SCN2A (p.R28C) previously reported in individuals with NDDs, however ,none of these variants meet PLP per these criteria. The SCN1A R28C variant is present in 0.003%; 45 alleles in gnomAD v4.1.
• PM1: Variant does not fall within a pathogenic enriched region.
• PM6: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PM2: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline