Submissions for variant NM_020822.3(KCNT1):c.1777G>A (p.Val593Met)

gnomAD frequency: 0.00003  dbSNP: rs779590747

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
CeGaT Center for Human Genetics Tuebingen	RCV000415957	SCV000493674	uncertain significance	not provided	2016-04-01	criteria provided, single submitter	clinical testing
GeneDx	RCV000606714	SCV000726463	likely benign	not specified	2018-01-19	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.
Ambry Genetics	RCV002318370	SCV000851617	uncertain significance	Inborn genetic diseases	2017-04-14	criteria provided, single submitter	clinical testing	The p.V593M variant (also known as c.1777G>A), located in coding exon 18 of the KCNT1 gene, results from a G to A substitution at nucleotide position 1777. The valine at codon 593 is replaced by methionine, an amino acid with highly similar properties. This variant did not co-segregate with disease in three individuals tested in our laboratory. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae	RCV001861460	SCV002206730	uncertain significance	Developmental and epileptic encephalopathy, 14; Autosomal dominant nocturnal frontal lobe epilepsy 5	2023-11-27	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 593 of the KCNT1 protein (p.Val593Met). This variant is present in population databases (rs779590747, gnomAD 0.06%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with KCNT1-related conditions. ClinVar contains an entry for this variant (Variation ID: 374766). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt KCNT1 protein function with a negative predictive value of 80%. 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.