ClinVar Miner

Submissions for variant NM_172107.4(KCNQ2):c.365C>T (p.Ser122Leu) (rs118192194)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000187851 SCV000241451 pathogenic not provided 2018-11-20 criteria provided, single submitter clinical testing The S122L missense change has been previously reported as a de novo change in an individual with neonatal seizures and developmental delay (Zhang et al., 2015). It has also been previously reported in a family with benign familial neonatal convulsions (BFNC) (Hunter et al., 2006). The variant segregated with the three affected individuals in the family and was not identified in three unaffected family members or in 400 controls (Hunter et al., 2006). The variant alters a highly conserved residue predicted to be predicted to be within the extracellular loop between the S1 and S2 transmembrane segments. While most previously reported pathogenic variants occur in the S4 transmembrane segment, functional studies suggest that the S122L slows the activation kinetics of the voltage-gated channel (Hunter et al., 2006). The S122L variant is not observed in large population cohorts (Lek et al., 2016). This variant is a non-conservative amino acid substitution of a polar Serine residue with a non-polar Leucine residue. Therefore this variant is classified as pathogenic.
Invitae RCV000692591 SCV000820421 pathogenic Early infantile epileptic encephalopathy 2019-11-04 criteria provided, single submitter clinical testing This sequence change replaces serine with leucine at codon 122 of the KCNQ2 protein (p.Ser122Leu). The serine residue is moderately conserved and there is a large physicochemical difference between serine and leucine. This variant is not present in population databases (ExAC no frequency). This variant has been reported to be de novo in individuals affected with early infantile epileptic encephalopathy (PMID: 26544041) and has also been reported to segregate with seizures in an autosomal dominant manner in several families (PMID: 16916607, 27602407). ClinVar contains an entry for this variant (Variation ID: 21787). Experimental studies have shown that this missense change results in slower electrophysiological activation than wild-type KCNQ2 in oocytes (PMID: 16916607). For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics,Fulgent Genetics RCV000763058 SCV000893543 likely pathogenic Benign familial neonatal seizures 1; Early infantile epileptic encephalopathy 7 2018-10-31 criteria provided, single submitter clinical testing
GeneReviews RCV000678078 SCV000041639 pathogenic Benign familial neonatal seizures 1 2016-03-31 no assertion criteria provided literature only BFNE (benign familial neonatal epilepsy). FS (febrile seizures) in later life; seizures until 7 years.

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