Total submissions: 2
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Victorian Clinical Genetics Services, |
RCV000578191 | SCV000680004 | likely pathogenic | Severe myoclonic epilepsy in infancy | 2017-08-29 | criteria provided, single submitter | clinical testing | A heterozygous missense variant was identified, NM_001165963.1(SCN1A):c.4040T>A in exon 21 of the SCN1A gene (chr2:166859226). This substitution is predicted to create a change of an isoleucine to an asparagine at amino acid position 1347, NP_001159435.1(SCN1A):p.(Ile1347Asn). The isoleucine at this position has high conservation and is located within an ion transport domain. Grantham assessment is likely deleterious due to both conservation and amino acid properties. In silico software predicts this variant to be disease causing. This variant has not been previously observed in our patient cohort, has not been previously reported in clinical cases and is not present in population databases. Subsequenct testing of parental samples indicated that this variant is due to a de novo event, paternity confirmed. Based on current information, this variant has been classified as LIKELY PATHOGENIC. |
Invitae | RCV003588648 | SCV004259582 | likely pathogenic | Early infantile epileptic encephalopathy with suppression bursts | 2024-01-09 | criteria provided, single submitter | clinical testing | This sequence change replaces isoleucine, which is neutral and non-polar, with asparagine, which is neutral and polar, at codon 1347 of the SCN1A protein (p.Ile1347Asn). This variant is not present in population databases (gnomAD no frequency). 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: 488378). 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 with a positive predictive value of 95%. This variant disrupts the p.Ile347 amino acid residue in SCN1A. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 27652284; 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 currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. |