Submissions for variant NM_001112741.2(KCNC1):c.959G>A (p.Arg320His)

dbSNP: rs727502818

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000149909	SCV000655548	pathogenic	Progressive myoclonic epilepsy type 7	2024-06-28	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 320 of the KCNC1 protein (p.Arg320His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with progressive myoclonus epilepsy (PME) (PMID: 25401298, 28380698). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 162519). 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 KCNC1 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects KCNC1 function (PMID: 25401298, 28380698). For these reasons, this variant has been classified as Pathogenic.
Undiagnosed Diseases Network, NIH	RCV000149909	SCV000837691	pathogenic	Progressive myoclonic epilepsy type 7	2018-02-07	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000149909	SCV000893873	pathogenic	Progressive myoclonic epilepsy type 7	2018-10-31	criteria provided, single submitter	clinical testing
Mendelics	RCV000149909	SCV001138241	pathogenic	Progressive myoclonic epilepsy type 7	2019-05-28	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002371993	SCV002690617	likely pathogenic	Inborn genetic diseases	2017-11-20	criteria provided, single submitter	clinical testing	The p.R320H variant (also known as c.959G>A), located in coding exon 2 of the KCNC1 gene, results from a G to A substitution at nucleotide position 959. The arginine at codon 320 is replaced by histidine, an amino acid with highly similar properties. This alteration has been identified de novo in multiple individuals with myoclonus, myoclonic epilepsy, and ataxia (Muona M et al. Nat. Genet., 2015 Jan;47:39-46; Oliver KL et al. Ann. Neurol., 2017 May;81:677-689; Nascimento FA et al. Epileptic Disord, 2016 Sep;18:135-138). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Athena Diagnostics	RCV003482236	SCV004229753	pathogenic	not provided	2023-08-02	criteria provided, single submitter	clinical testing	This variant has been identified in multiple unrelated individuals with clinical features associated with this gene and appears to occur de novo in multiple individuals. This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). Assessment of experimental evidence suggests this variant results in abnormal protein function. (PMID: 33735526, 29894724, 25401298)
OMIM	RCV000149909	SCV000196760	pathogenic	Progressive myoclonic epilepsy type 7	2015-01-01	no assertion criteria provided	literature only