Submissions for variant NM_020822.3(KCNT1):c.1694G>A (p.Arg565His) (rs769855266)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000603730	SCV000718161	likely benign	not specified	2017-04-14	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Invitae	RCV000815790	SCV000956262	uncertain significance	Early infantile epileptic encephalopathy 14; Epilepsy, nocturnal frontal lobe, 5	2018-12-17	criteria provided, single submitter	clinical testing	This sequence change replaces arginine with histidine at codon 565 of the KCNT1 protein (p.Arg565His). The arginine residue is moderately conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs769855266, ExAC 0.008%). This variant has not been reported in the literature in individuals with KCNT1-related conditions. ClinVar contains an entry for this variant (Variation ID: 508726). 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 tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.