ClinVar Miner

Submissions for variant NM_001165963.4(SCN1A):c.68C>A (p.Ala23Glu)

dbSNP: rs139397227
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000188916 SCV000242546 uncertain significance not provided 2022-03-25 criteria provided, single submitter clinical testing Reported previously as a variant of uncertain significance, inherited from an unaffected father, in a patient with hypotonia, global developmental delay, epilepsy, and biochemically confirmed PIGN-related disorder; however, this SCN1A variant co-occurred with compound heterozygous variants in the PIGN gene that were thought to be responsible for the phenotype (Thiffault et al., 2017); Not observed at significant frequency in large population cohorts (gnomAD); Missense variants in this gene are often considered pathogenic (HGMD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This substitution is predicted to be within the N-terminal cytoplasmic domain; This variant is associated with the following publications: (PMID: 29096607)
Labcorp Genetics (formerly Invitae), Labcorp RCV001061719 SCV001226471 uncertain significance Early infantile epileptic encephalopathy with suppression bursts 2024-12-22 criteria provided, single submitter clinical testing This sequence change replaces alanine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 23 of the SCN1A protein (p.Ala23Glu). This variant is present in population databases (rs139397227, gnomAD 0.006%). This variant has not been reported in the literature in individuals affected with SCN1A-related conditions. ClinVar contains an entry for this variant (Variation ID: 206800). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt SCN1A protein function with a positive predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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