ClinVar Miner

Submissions for variant NM_001165963.4(SCN1A):c.519T>G (p.Ile173Met)

dbSNP: rs1283681963
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Génétique des Maladies du Développement, Hospices Civils de Lyon RCV001353144 SCV001548291 likely pathogenic Seizure 2021-04-01 criteria provided, single submitter clinical testing predicted pathogenic. Good geno/pheno correlation. 1 in gnomAD v2.1
GeneDx RCV003442866 SCV004170537 likely pathogenic not provided 2023-10-25 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (gnomAD); The majority of missense variants in this gene are considered pathogenic (HGMD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This substitution is predicted to be within the transmembrane segment S2 of the first homologous domain
Invitae RCV003771032 SCV004620335 uncertain significance Early infantile epileptic encephalopathy with suppression bursts 2023-10-03 criteria provided, single submitter clinical testing This sequence change replaces isoleucine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 173 of the SCN1A protein (p.Ile173Met). This variant is present in population databases (no rsID available, gnomAD 0.0009%). 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: 1048588). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt SCN1A protein function. This variant disrupts the p.Ile173 amino acid residue in SCN1A. Other variant(s) that disrupt this residue have been determined to be pathogenic (Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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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