Submissions for variant NM_004974.4(KCNA2):c.881G>A (p.Arg294His)

dbSNP: rs886041761

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000339475	SCV000330512	pathogenic	not provided	2022-02-03	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect: significantly reduced current amplitudes in X. laevis oocytes, with a dominant-negative effect observed when co-expressed with wild type (Helgib et al., 2016; Manole et al., 2017); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 27543892, 28032718, 27513193, 33802230, 34445196)
CeGaT Center for Human Genetics Tuebingen	RCV000339475	SCV000493332	pathogenic	not provided	2024-03-01	criteria provided, single submitter	clinical testing	KCNA2: PS4, PM2, PM6, PP2, PP3, PS3:Supporting
Ambry Genetics	RCV000622695	SCV000740702	pathogenic	Inborn genetic diseases	2020-12-16	criteria provided, single submitter	clinical testing	The c.881G>A (p.R294H) alteration is located in exon 3 (coding exon 1) of the KCNA2 gene. This alteration results from a G to A substitution at nucleotide position 881, causing the arginine (R) at amino acid position 294 to be replaced by a histidine (H). Based on data from the Genome Aggregation Database (gnomAD), the KCNA2 c.881G>A alteration was not observed, with coverage at this position. The KCNA2 c.881G>A (p.R294H) alteration has been reported in six individuals from three unrelated families with hereditary spastic paraplegia (Helbig, 2016; Manole, 2017). In one patient, the alteration was confirmed de novo. A seventh patient was reported with the de novo c.881G>A (p.R294H) alteration, who had ataxia and intellectual disability; she exhibited no signs of spasticity at age 20 years (Helbig, 2016). She also had early onset absence epilepsy, which may be unrelated to the KCNA2 alteration. The p.R294 amino acid is completely conserved in available vertebrate species. The p.R294 amino acid is located in the S4 transmembrane segment of the Kv1.2 channel, which forms the voltage sensor domain (Tombola, 2005; Delemotte, 2010). This arginine is the first of six evenly spaced and highly conserved positively charged amino acid residues (p.R294, p.R297, p.R300, p.R303, p.K306, p.R309), which act as "gating charges" and respond to a voltage difference across the cell membrane, allowing Kv1.2 to assume either an open or closed conformation that allows potassium ions to flow through the channel based on their electrochemical gradient (Seoh, 1996; Aggarwal, 1996; Long, 2005). Functional analysis of the p.R294H alteration in Xenopus oocytes revealed that the variant results in a loss of channel function with a dominant-negative effect (Helbig, 2016; Manole, 2017). The p.R294H alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000706154	SCV000835190	pathogenic	Developmental and epileptic encephalopathy, 32	2024-01-31	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 294 of the KCNA2 protein (p.Arg294His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with autosomal dominant spastic paraplegia, ataxia, intellectual disability and/or epilepsy (PMID: 27543892, 28032718, 33802230). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 280584). 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 expected to disrupt KCNA2 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects KCNA2 function (PMID: 27543892, 28032718). For these reasons, this variant has been classified as Pathogenic.
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000339475	SCV001446499	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
Molecular Medicine for Neurodegenerative and Neuromuscular Diseases Unit, IRCCS Fondazione Stella Maris	RCV000706154	SCV001519146	pathogenic	Developmental and epileptic encephalopathy, 32	2021-01-04	criteria provided, single submitter	research
Undiagnosed Diseases Network, NIH	RCV000706154	SCV001827221	pathogenic	Developmental and epileptic encephalopathy, 32	2021-06-04	criteria provided, single submitter	clinical testing	Both GOF and LOF variants have been described in KCNA2. This patient has a known LOF variant associated with spasticity, autism like features, and very mild developmental delay. The onset of spasticity associated with KCNA2 variants has ranged from 2-20 years of age. Clinical seizures are uncommon with LOF variants, but epileptiform discharges have been observed more frequently.
Institute of Human Genetics, University of Leipzig Medical Center	RCV000706154	SCV001934289	likely pathogenic	Developmental and epileptic encephalopathy, 32	2023-09-04	criteria provided, single submitter	clinical testing	Criteria applied: PS4_MOD,PS3_SUP,PM2_SUP,PP2,PP3
Genetic Services Laboratory, University of Chicago	RCV000339475	SCV002064334	likely pathogenic	not provided	2017-09-15	criteria provided, single submitter	clinical testing
Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	RCV000706154	SCV002764742	pathogenic	Developmental and epileptic encephalopathy, 32	2020-09-11	criteria provided, single submitter	clinical testing
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV000339475	SCV005198512	pathogenic	not provided	2023-02-07	criteria provided, single submitter	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000339475	SCV002035677	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000339475	SCV002037553	likely pathogenic	not provided		no assertion criteria provided	clinical testing