Total submissions: 3
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Gene |
RCV000419099 | SCV000533469 | likely pathogenic | not provided | 2016-11-01 | criteria provided, single submitter | clinical testing | The D366H variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. It was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The D366H variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution alters a conserved position predicted to be within the pore forming loop between the S5 and S6 transmembrane segments of the first homologous domain. Additionally, a missense variant at the same residue (D366E) has been reported in the Human Gene Mutation Database in association with SCN1A-related disorders (Stenson et al., 2014). In silico analysis predicts this variant is probably damaging to the protein structure/function. Therefore, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded. |
Ce |
RCV000419099 | SCV001152518 | likely pathogenic | not provided | 2018-08-01 | criteria provided, single submitter | clinical testing | |
Invitae | RCV002522586 | SCV003353879 | pathogenic | Early infantile epileptic encephalopathy with suppression bursts | 2023-05-24 | criteria provided, single submitter | clinical testing | This sequence change replaces aspartic acid, which is acidic and polar, with histidine, which is basic and polar, at codon 366 of the SCN1A protein (p.Asp366His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of Dravet syndrome (Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 390594). 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant disrupts the p.Asp366 amino acid residue in SCN1A. Other variant(s) that disrupt this residue have been observed in individuals with SCN1A-related conditions (PMID: 18413471), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. |