Total submissions: 3
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Gene |
RCV000725077 | SCV000240514 | uncertain significance | not provided | 2018-09-11 | criteria provided, single submitter | clinical testing | p.His443Asp (CAC>GAC): c.1327 C>G in exon 5 of the CHRNA4 gene (NM_000744.5)The His443Asp missense change has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. It was not observed in approximately 6,200 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. This variant is a non-conservative amino acid substitution of a positively charged Histidine residue with a negatively charged Aspartic acid residue. However, His443Asp alters a poorly conserved position in the topological domain of the CHRNA4 protein and in silico analysis predicts this variant likely has a benign effect on the protein structure/function. In addition, the His443Asp amino acid substitution does not occur within the transmembrane region of the protein where most pathogenic missense mutations have been identified in association with epilepsy (Steinlein et al., 2010). Therefore, based on the currently available information, it is unclear whether His443Asp is a disease-causing mutation or a rare benign variant. The variant is found in EPILEPSY panel(s). |
Eurofins Ntd Llc |
RCV000725077 | SCV000333802 | uncertain significance | not provided | 2015-08-06 | criteria provided, single submitter | clinical testing | |
Invitae | RCV000524714 | SCV000658067 | uncertain significance | Autosomal dominant nocturnal frontal lobe epilepsy | 2023-04-26 | criteria provided, single submitter | clinical testing | This variant is present in population databases (rs796052319, gnomAD 0.01%). 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. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant  is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 205027). This variant has not been reported in the literature in individuals affected with CHRNA4-related conditions. This sequence change replaces histidine, which is basic and polar, with aspartic acid, which is acidic and polar, at codon 443 of the CHRNA4 protein (p.His443Asp). |