Submissions for variant NM_004974.4(KCNA2):c.1214C>T (p.Pro405Leu)

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000407449	SCV000329995	pathogenic	not provided	2021-11-17	criteria provided, single submitter	clinical testing	Published functional study demonstrates loss of channel function through a dominant negative effect (Syrbe et al., 2015); Not observed at significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25997620, 30182498, 29050392, 28600779, 28806589, 30055040, 28488083, 29895856, 27864847, 33232902, 33802230, 33355533, 34576077, 31932120, 25751627)
Génétique des Maladies du Développement, Hospices Civils de Lyon	RCV000170511	SCV001164173	pathogenic	Developmental and epileptic encephalopathy, 32	2017-08-09	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000170511	SCV001215242	pathogenic	Developmental and epileptic encephalopathy, 32	2024-12-02	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 405 of the KCNA2 protein (p.Pro405Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with epileptic encephalopathy (PMID: 25751627). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 190325). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on KCNA2 protein function. Experimental studies have shown that this missense change affects KCNA2 function (PMID: 25751627). For these reasons, this variant has been classified as Pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV000407449	SCV001248404	pathogenic	not provided	2021-09-01	criteria provided, single submitter	clinical testing
Blueprint Genetics	RCV000170511	SCV001426145	pathogenic	Developmental and epileptic encephalopathy, 32	2018-04-19	criteria provided, single submitter	clinical testing
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000407449	SCV001447211	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Leipzig Medical Center	RCV000170511	SCV001950005	likely pathogenic	Developmental and epileptic encephalopathy, 32	2021-06-16	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000170511	SCV002023206	pathogenic	Developmental and epileptic encephalopathy, 32	2023-01-10	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002517634	SCV003745333	pathogenic	Inborn genetic diseases	2021-06-30	criteria provided, single submitter	clinical testing	The c.1214C>T (p.P405L) alteration is located in exon 3 (coding exon 1) of the KCNA2 gene. This alteration results from a C to T substitution at nucleotide position 1214, causing the proline (P) at amino acid position 405 to be replaced by a leucine (L). Based on data from the Genome Aggregation Database (gnomAD), the KCNA2 c.1214C>T alteration was not observed, with coverage at this position. This alteration has been reported in multiple unrelated patients with epileptic encephalopathy and is the most common recurrent variant in KCNA2 (Syrbe, 2015; Masnada, 2017; Sachdev, 2017; Miao, 2018; Gong, 2020). This amino acid position is highly conserved in available vertebrate species. Functional characterization of the P405L alteration with a voltage-clamp oocyte testing system found a dramatic reduction of current amplitudes with a dominant negative effect (Syrbe, 2015). The p.P405L alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic.
Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre	RCV000170511	SCV004801198	pathogenic	Developmental and epileptic encephalopathy, 32	2024-03-14	criteria provided, single submitter	research
Génétique des Maladies du Développement, Hospices Civils de Lyon	RCV004546448	SCV005043046	pathogenic	Seizure	2023-12-27	criteria provided, single submitter	clinical testing
OMIM	RCV000170511	SCV000222943	pathogenic	Developmental and epileptic encephalopathy, 32	2015-04-01	no assertion criteria provided	literature only
Laboratory of Molecular Genetics (Pr. Bezieau's lab), CHU de Nantes	RCV000407449	SCV000778262	pathogenic	not provided	2017-06-07	no assertion criteria provided	clinical testing
Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City	RCV000170511	SCV001132802	pathogenic	Developmental and epileptic encephalopathy, 32	2019-01-29	no assertion criteria provided	clinical testing