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]
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  • Gene obtained from curated document aligns with the Allele Registry but not with ClinVar data
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Variant: NM_001330260.2(SCN8A):c.5615G>A (p.Arg1872Gln)

CA10586302

253297 (ClinVar)

Gene: SCN8A
Condition: complex neurodevelopmental disorder
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: d0375b89-030e-4aa3-9ef1-bf3969e1e2b1

HGVS expressions

NM_001330260.2:c.5615G>A
NM_001330260.2(SCN8A):c.5615G>A (p.Arg1872Gln)
NC_000012.12:g.51807101G>A
CM000674.2:g.51807101G>A
NC_000012.11:g.52200885G>A
CM000674.1:g.52200885G>A
NC_000012.10:g.50487152G>A
NG_021180.2:g.220866G>A
NG_021180.3:g.222144G>A
ENST00000354534.11:c.5615G>A
ENST00000627620.5:c.5615G>A
ENST00000662684.1:c.5615G>A
ENST00000668547.1:c.5492G>A
ENST00000354534.10:c.5615G>A
ENST00000355133.7:c.5492G>A
ENST00000545061.5:c.5492G>A
ENST00000599343.5:c.5648G>A
ENST00000627620.2:c.5615G>A
NM_001177984.2:c.5492G>A
NM_014191.3:c.5615G>A
NM_001330260.1:c.5615G>A
NM_001369788.1:c.5492G>A
NM_014191.4:c.5615G>A
NM_001177984.3:c.5492G>A

Pathogenic

Met criteria codes 6
PM6 PM2_Supporting PM5_Strong PP3_Moderate PS4 PS3

Evidence Links 1

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.5615G>A variant in SCN8A is a missense variant predicted to cause a subtitution of arginine by glutamine at amino acid 1872 (p.Arg1872Gln). This variant has been reported as de novo in at least 3 individuals with unconfirmed parental relationships (PMIDs: 2664715, 28333917, 28387369) (PM6) and at least an additional 8 individuals without informative segregation data available (PMIDs: 25568300, 29655203, 29930392, 32509551, 34395220, 30968951) (PS4). Multiple other amino acid substitutions at the same amino acid position have been previously reported and meet pathogenic per these criteria (p.Arg1872Gly, p.Arg1872Trp, p.Arg1872Leu) (PM5). Heterologous expression with voltage clamping assay has shown significant hyperpolarizing shift in voltage dependence of activation and significant depolarizing shift of voltage dependence of fast inactivation (PS3). The variant is rare (1 allele) in the population database, gnomAD v2.1.1 (PM2_Supporting). In summary, this variant meets the criteria to be classified as pathogenic for autosomal dominant complex neurodevelopmental disorder based on the ACMG/AMP criteria applied, as specified by the ClinGen Epilepsy Sodium Channel VCEP: PS4, PM6, PM5, PS3, PM2_Supporting (version 1.0; approved 5/23/23).
Met criteria codes
PM6
The variant was identified in 3 probands in the literature including from the following citations: PMID: 2664715, a proband with early onset intractable epileptic encephalopathy, developmental regression, and progressive cerebellar atrophy with both parents testing negative via Sanger sequencing; PMID: 28333917, a proband with complex pediatric onset neurodevelopmental disorder with negative parental testing; PMID: 28387369, a proband with early infantile epileptic encephalopathy with negative parental testing.
PM2_Supporting
One allele with a minimum of 10,000 alleles assess in gnomAD.
PM5_Strong
SCN8A: p.Arg1872Gly, p.Arg1872Trp, p.Arg1872Leu are all pathogenic variants.
PP3_Moderate
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS4
The variant was identified in 8 unrelated probands in the literature including from the following citations: PMID 25568300, two probands with epilepsy; PMID 29655203, one proband with epilepsy and/or neurodevelopmental disorder; PMID 29930392, one proband with epilepsy and brain malformations; PMID 32509551, two probands with infantile-onset epileptic encephalopathy; PMID 34395220, one proband with early infantile epileptic encephalopathy; PMID: 30968951, siblings with epilepsy with mosaic father (counted as one case).
PS3
The variant was studied via patch clamping in ND7/23 cells and found to have mild increase in peak current (criterion not met); no significant difference in persistent current; significant hyperpolarizing shift in voltage dependence of activation; significant depolarizing shift of voltage dependence of fast inactivation.
The variant was studied via patch clamping in ND7/23 cells and found to have mild increase in peak current (criterion not met); no significant difference in persistent current; significant hyperpolarizing shift in voltage dependence of activation; significant depolarizing shift of voltage dependence of fast inactivation. PubMed:26900580
Approved on: 2024-05-09
Published on: 2024-05-09
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