Submissions for variant NM_172107.4(KCNQ2):c.365C>T (p.Ser122Leu)

dbSNP: rs118192194

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000187851	SCV000241451	pathogenic	not provided	2022-02-16	criteria provided, single submitter	clinical testing	Published functional studies demonstrate slowed activation kinetics of the voltage-gated channel (Hunter et al., 2006); Missense variants in this gene are often considered pathogenic (HGMD); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This substitution is predicted to be within the extracellular loop between the S1 and S2 transmembrane segments; This variant is associated with the following publications: (PMID: 33098118, 16916607, 18238816, 28074849, 28082013, 27602407, 18698150, 28488083, 26544041, 34070668, 34711204, 33659638)
Invitae	RCV000692591	SCV000820421	pathogenic	Early infantile epileptic encephalopathy with suppression bursts	2024-01-06	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 122 of the KCNQ2 protein (p.Ser122Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with early infantile epileptic encephalopathy (PMID: 16916607, 26544041, 27602407). 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: 21787). 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 KCNQ2 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects KCNQ2 function (PMID: 16916607). For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV000763058	SCV000893543	likely pathogenic	Seizures, benign familial neonatal, 1; Developmental and epileptic encephalopathy, 7	2018-10-31	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001270883	SCV001451662	pathogenic	KCNQ2-Related Disorders	2019-06-26	criteria provided, single submitter	clinical testing	The KCNQ2 c.365C>T (p.Ser122Leu) variant is a missense variant that has been reported in three studies, in which it is found in a heterozygous state in a total of six individuals, of whom three are unrelated (Hunter et al. 2006; Zhang et al. 2015; Millichap et al. 2016). One individual had early onset epileptic encephalopathy and five had benign familial neonatal seizures (BFNS). The p.Ser122Leu variant was found in a father with BNFS and his two affected sons, but was absent from three unaffected family members (Hunter et al. 2006). Additionally, a pair of siblings with BFNS were found to be heterozygous for the variant, but parental testing was not performed (Millichap et al. 2016). The variant was absent from 400 control subjects and is not found in the Genome Aggregation Database despite being in a region of good sequence coverage, so the variant is presumed to be rare. Electrophysiology studies were performed in Xenopus oocytes to assess the effect of the p.Ser122Leu variant. A shift in voltage dependence of activation was observed resulting in reduction of activation kinetics when compared to wild type (Hunter et al. 2006). Based on the collective evidence and the application of ACMG criteria, the p.Ser122Leu variant is classified as pathogenic for KCNQ2-related disorders.
Neuberg Supratech Reference Laboratories Pvt Ltd, Neuberg Centre for Genomic Medicine	RCV002510564	SCV002820280	pathogenic	Developmental and epileptic encephalopathy, 7		criteria provided, single submitter	clinical testing	The missense variant p.S122L in KCNQ2 (NM_172107.4) has been previously reported in heterozygous state in affected indviduals with both epileptic encephalopathy and benign neonatal seizures (Zhang Y et al, Millichap J et al). Experimental studies show slower electrophysiological activation as compared to wild type (Hunter J et al). The variant has been deposited to ClinVar as Pathogenic. The p.S122L variant is novel (not in any individuals) in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. The p.S122L missense variant is predicted to be damaging by both SIFT and PolyPhen2. The nucleotide c.365 in KCNQ2 is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic
GeneReviews	RCV000678078	SCV000041639	not provided	Seizures, benign familial neonatal, 1		no assertion provided	literature only	BFNE (benign familial neonatal epilepsy). FS (febrile seizures) in later life; seizures until 7 years.
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000187851	SCV001808441	pathogenic	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000187851	SCV001932516	pathogenic	not provided		no assertion criteria provided	clinical testing