ClinVar Miner

Submissions for variant NM_020822.3(KCNT1):c.2882G>A (p.Arg961His) (rs200694691)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Genetic Services Laboratory,University of Chicago RCV000117366 SCV000151549 uncertain significance not provided 2013-10-09 criteria provided, single submitter clinical testing
Neurogenetics Laboratory - MEYER,AOU Meyer RCV000416953 SCV000494566 uncertain significance Focal epilepsy 2016-11-16 criteria provided, single submitter clinical testing
GeneDx RCV000117366 SCV000582127 likely pathogenic not provided 2018-05-09 criteria provided, single submitter clinical testing The R961H variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The R961H variant is not observed in large population cohorts (Lek et al., 2016). This variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. However, in-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. In addition, R961H has been observed as an apparently de novo variant in a patient with seizures previously tested at GeneDx.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000117366 SCV000702631 uncertain significance not provided 2018-08-14 criteria provided, single submitter clinical testing
Athena Diagnostics Inc RCV000117366 SCV000842548 uncertain significance not provided 2017-11-24 criteria provided, single submitter clinical testing
Invitae RCV001061890 SCV001226652 likely pathogenic Early infantile epileptic encephalopathy 14; Epilepsy, nocturnal frontal lobe, 5 2019-04-29 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 961 of the KCNT1 protein (p.Arg961His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals affected with epileptic encephalopathy (PMID: 29186148, Invitae) and it has been observed de novo in at least one of these individuals (Invitae). ClinVar contains an entry for this variant (Variation ID: 129360). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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.

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