Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000522556 | SCV000621725 | uncertain significance | not provided | 2017-10-19 | criteria provided, single submitter | clinical testing | The c.1216 A>G variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. This variant is not observed in large population cohorts (Lek et al., 2016). Severalin-silico splice prediction models predict that c.1216 A>G may destroy or damage the natural splice donor site for exon 10 and lead to abnormal gene splicing; however, in the absence of RNA/functional studies, the actual effect of c.1216 A>G on splicing is unknown. If c.1216 A>G does not alter splicing, it will result in the R406G missense change, which is a non-conservative amino acid substitution that 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 that is predicted to be within theC-terminal cytoplasmic domain. In silico analysis predicts this variant is probably damaging to theprotein structure/function. Therefore, based on the currently available information, it is unclearwhether this variant is a pathogenic variant or a rare benign variant. |
| Invitae | RCV000702823 | SCV000831694 | uncertain significance | Early infantile epileptic encephalopathy with suppression bursts | 2022-07-12 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 406 of the KCNQ2 protein (p.Arg406Gly). 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 452880). This variant has not been reported in the literature in individuals affected with KCNQ2-related conditions. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. |