Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000485665 | SCV000570126 | uncertain significance | not provided | 2020-10-30 | criteria provided, single submitter | clinical testing | Not observed in large population cohorts (Lek et al., 2016); The majority of missense variants in this gene are considered pathogenic (Stenson et al., 2014); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This substitution is predicted to be within the intracellular loop between the S4 and S5 transmembrane segments of the fourth homologous domain.; Published functional studies suggest this variant alters the inactivation time constant as well as the gating current immobilization of the sodium channel, however additional studies are needed to validate the functional effect of this variant in vivo (Kuhn et al., 1999); Identified in an individual with epileptic encephalopathy in the published literature who inherited the variant from a parent; however, clinical information about the parent was not provided (Zhu et al., 2017); This variant is associated with the following publications: (PMID: 11118488, 11567038, 10435996, 29186148) |
| Clinical Genomics Laboratory, |
RCV004555864 | SCV005045140 | uncertain significance | Developmental and epileptic encephalopathy, 13 | 2023-12-17 | criteria provided, single submitter | clinical testing | The SCN8A c.4913G>A (p.Arg1638His) variant, to our knowledge, has not been reported in the medical literature but has been reported in the ClinVar database as a germline variant of uncertain significance by one submitter. This variant is absent from the general population (gnomAD v.2.1.1), indicating it is not a common variant. This variant occurs in a predicted alpha helix in a transmembrane domain (Talwar D and Hammer MF. PMID: 34353676) and computational predictors indicate that the variant is damaging, evidence that correlates with impact to SCN8A function. Additionally, another variant in the analogous amino acid in the highly related sodium channel gene SCN1A, c.4970G>A (p.Arg1657His), has been detected in an affected individual and is considered pathogenic (ClinVar Variation ID: 68559). However, due to limited information, and based on ACMG/AMP guidelines for variant interpretation (Richards S et al., PMID: 25741868), the clinical significance of this variant is uncertain at this time. |