Submissions for variant NM_004977.3(KCNC3):c.1268G>A (p.Arg423His)

dbSNP: rs797044872

Total submissions: 20

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000190682	SCV000244122	pathogenic	Inborn genetic diseases	2021-11-16	criteria provided, single submitter	clinical testing	The c.1268G>A (p.R423H) alteration is located in exon 2 (coding exon 2) of the KCNC3 gene. This alteration results from a G to A substitution at nucleotide position 1268, causing the arginine (R) at amino acid position 423 to be replaced by a histidine (H). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This alteration has been reported in multiple unrelated patients with early-onset slowly-progressive ataxia (Figueroa, 2010; Duarri, 2015; Khare, 2017). This amino acid position is highly conserved in available vertebrate species. The p.R423H alteration has been shown in multiple independent studies to negatively affect Kv3.3 channel functioning by suppressing current amplitude (Figueroa, 2010), significantly altering gating (Minassian, 2012), or resulting in altered glycosylation and aberrant retention of the mutant channels in the anterograde and/or endosomal vesicles instead of at the plasma membrane (Khare, 2017). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic.
GeneDx	RCV000277864	SCV000330001	pathogenic	not provided	2022-02-10	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect, resulting in loss of channel activity consistent with a strong dominant negative effect (Figueroa et al., 2010; Duarri et al., 2015); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25356970, 23734863, 22289912, 19953606, 26795593, 21479265, 28216058, 28467418, 25756792, 33624863)
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000613729	SCV000744003	pathogenic	Spinocerebellar ataxia type 13	2014-10-08	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000277864	SCV000842509	pathogenic	not provided	2018-04-04	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000277864	SCV001246457	pathogenic	not provided	2019-12-01	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000277864	SCV001378390	pathogenic	not provided	2024-10-22	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 423 of the KCNC3 protein (p.Arg423His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with spinocerebellar ataxia (PMID: 19953606, 25756792, 28467418). 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: 208671). 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) indicates that this missense variant is expected to disrupt KCNC3 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects KCNC3 function (PMID: 19953606, 22289912, 25756792, 28467418). For these reasons, this variant has been classified as Pathogenic.
Institute of Human Genetics, University of Leipzig Medical Center	RCV000613729	SCV001429420	pathogenic	Spinocerebellar ataxia type 13	2018-11-15	criteria provided, single submitter	clinical testing
Molecular Medicine for Neurodegenerative and Neuromuscular Diseases Unit, IRCCS Fondazione Stella Maris	RCV000613729	SCV001519147	pathogenic	Spinocerebellar ataxia type 13	2021-01-04	criteria provided, single submitter	research
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000277864	SCV001905584	pathogenic	not provided	2021-09-15	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000277864	SCV002064519	pathogenic	not provided	2021-02-17	criteria provided, single submitter	clinical testing	DNA sequence analysis of the KCNC3 gene demonstrated a sequence change, c.1268G>A, in exon 2 that results in an amino acid change, p.Arg423His. This sequence change is absent in the gnomAD population database. This sequence change has been previously described in individuals and families with ataxia or spinocerebellar ataxia 13 (PMIDs: 19953606, 25756792, 28467418, 28216058). The p.Arg423His change affects a highly conserved amino acid residue located in the S4 transmembrane segment of the KCNC3 protein. It appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Functional studies show p.Arg423His disrupts the channel activity of the KCNC3 protein and demonstrates a dominant-negative effect (PMIDs: 19953606, 25756792, 28467418). These collective evidences suggest this p.Arg423His change is pathogenic.
Molecular Genetics, Royal Melbourne Hospital	RCV000613729	SCV002503864	pathogenic	Spinocerebellar ataxia type 13	2020-10-30	criteria provided, single submitter	clinical testing	This sequence change is predicted to replace arginine with histidine at codon 423 of the KCNC3 protein (p.(Arg423His)). The arginine residue is invariant across species (100 vertebrates, UCSC), and is located in the S4 transmembrane segment in the ion transport domain. There is a small physicochemical difference between arginine and histidine. The variant is absent in a large population cohort (rs797044872, gnomAD v2.1 and v3.0). This variant has been identified in multiple individuals with early-onset non-progressive spinocerebellar ataxia, with at least two individuals assumed de novo (PMID: 19953606 , 25756792, 28216058, 28467418). The variant segregates with affected status in multiple families (PMID: 19953606, 28216058, 28467418). A zebrafish model of the variant recapitulates the cerebellar degeneration, and demonstrated differential affects on Purkinje cell excitability, maturation, and viability to an adult-onset associated variant (PMID: 32644043). Multiple lines of computational evidence predict a deleterious effect for the missense substitution (5/5 algorithms). Based on the classification scheme RMH Modified ACMG Guidelines v1.3.0, this variant is classified as PATHOGENIC. Following criteria are met: PS3, PM6_Strong, PP1_Strong, PS4_Moderate, PM2_Supporting, PP3.
3billion, Medical Genetics	RCV000613729	SCV002521695	pathogenic	Spinocerebellar ataxia type 13	2022-05-22	criteria provided, single submitter	clinical testing	The variant is not observed in the gnomAD v2.1.1 dataset. Missense changes are a common disease-causing mechanism. Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID:19953606, 22289912, 25756792, 28467418). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.92; 3Cnet: 0.72). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000208671). The variant has been previously reported as de novo (PMID: 28467418). and observed in multiple (>3) similarly affected unrelated individuals (PMID:19953606, 28467418). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000613729	SCV002557660	pathogenic	Spinocerebellar ataxia type 13	2022-02-02	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Dominant negative and gain of function are known mechanisms of disease in this gene and are associated with Spinocerebellar ataxia 13 (MIM#605259). (PMIDs: 22289912, 26442672, GeneReviews). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0115 - Variants in this gene are known to have variable expressivity. Age of onset (congenital or adult-onset), phenotype and disease progression depend on the location of the variant and its action on the channel, Kv3.3. (PMID: 25756792; 26442672, GeneReviews). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to histidine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools. Very high conservation with a minor amino acid change. (SP) 0600 - Variant is located in the annotated transmembrane S4 domain (UniProt, PMID: 26442672). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported as pathogenic in multiple individuals with early onset non-progressive spinocerebellar ataxia. It has been shown to segregate with disease in several families, and there have been at least two reports of de novo cases (ClinVar, LOVD3, PMID: 19953606, 21479265, 25756792, 28467418). (SP) 0902 - This variant has moderate evidence for segregation with disease (PMID: 28467418). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Targeted expression in zebrafish and drosophila models have demonstrated disrupted axonal pathfinding and neurodegeneration consistent with the neurodevelopmental presentations of disease in patients (PMIDs: 21543613, 30862666, 28467418). In addition, patch clamp studies of this variant expressed in Xenopus oocytes have shown significant loss of Kv3.3 channel activity, reduced current amplitude and cell surface expression. (PMIDs: 19953606, 22289912, 25756792). NB. However, patch clamp assays have been shown to be unreliable; therefore results from these studies are used with caution during variant classification. (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Institute of Human Genetics, Clinical Exome/Genome Diagnostics Group, University Hospital Bonn	RCV000613729	SCV002577374	pathogenic	Spinocerebellar ataxia type 13	2022-08-05	criteria provided, single submitter	clinical testing
Neuberg Centre For Genomic Medicine, NCGM	RCV000613729	SCV004176433	pathogenic	Spinocerebellar ataxia type 13	2023-02-14	criteria provided, single submitter	clinical testing	The missense c.1268G>A(p.Arg423His) variant in KCNC3 gene has been reported in heterozygous state in multiple individuals affected with KCNC3 related disorders (Khare S, et. al., 2017; Coutelier M, et. al., 2017; Duarri A, et. al., 2015). Functional studies show p.Arg423His disrupts the channel activity of the KCNC3 protein and demonstrates a dominant-negative effect (Figueroa KP, et. al., 2010). The p.Arg423His variant is novel (not in any individuals) in gnomAD Exomes and 1000 Genomes. This variant has been reported to the ClinVar database as Pathogenic (multiple submissions). The amino acid change p.Arg423His in KCNC3 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Arg at position 423 is changed to a His changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Pathogenic.
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV000277864	SCV005198516	pathogenic	not provided	2024-02-20	criteria provided, single submitter	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000613729	SCV000733909	pathogenic	Spinocerebellar ataxia type 13		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000277864	SCV001807226	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000277864	SCV001952775	pathogenic	not provided		no assertion criteria provided	clinical testing
O&I group, Department of Genetics, University Medical Center of Groningen	RCV000613729	SCV001960829	pathogenic	Spinocerebellar ataxia type 13	2021-07-22	no assertion criteria provided	research