ClinVar Miner

Submissions for variant NM_004975.4(KCNB1):c.934C>T (p.Arg312Cys) (rs886039396)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000255550 SCV000321795 pathogenic not provided 2016-05-02 criteria provided, single submitter clinical testing The R312C pathogenic variant in the KCNB1 has been reported previously as a de novo variant in an individual with epileptic encephalopathy (Kearney et al., 2015). 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 R312C 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 occurs at a conserved position predicted to be within the voltage-sensor transmembrane segment S4 of the KCNB1 protein, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Functional studies suggest that the R312C variant results in reduced channel activity and current as well as altering the voltage dependence of channel inactivation (Kearney et al., 2015).
Invitae RCV000528443 SCV000655445 likely pathogenic Epileptic encephalopathy, early infantile, 26 2017-08-25 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 312 of the KCNB1 protein (p.Arg312Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with KCNB1-related disease. However, family studies have indicated that this variant was not present in the parents of an individual with developmental delay and early-onset seizures, which suggests that it was de novo in that affected individual (Invitae). ClinVar contains an entry for this variant (Variation ID: 265207). 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, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.
Génétique des Maladies du Développement, Hospices Civils de Lyon RCV000528443 SCV000890019 likely pathogenic Epileptic encephalopathy, early infantile, 26 2018-05-28 criteria provided, single submitter clinical testing
Laboratoire de Génétique Moléculaire Institut de Recherche Necker Enfants Malades,CHU Paris - Hôpital Necker-Enfants Malades RCV000782147 SCV000920611 pathogenic Intellectual disability 2019-03-01 criteria provided, single submitter clinical testing

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