ClinVar Miner

Submissions for variant NM_172107.3(KCNQ2):c.601C>T (p.Arg201Cys) (rs796052623)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Baylor Miraca Genetics Laboratories, RCV000679892 SCV000807302 uncertain significance Benign familial neonatal seizures 1 2017-09-01 criteria provided, single submitter clinical testing Likely pathogenicity based on finding it once in our laboratory de novo in a 6-month-old female with motor delays, hypotonia, epilepsy (clinically thought to be early infantile myoclonic encephalopathy, onset at day 2 of life, with apneic episodes, controlled by medication but with onset of myoclous), nystagmus
CeGaT Praxis fuer Humangenetik Tuebingen RCV000187858 SCV000892664 likely pathogenic not provided 2018-09-30 criteria provided, single submitter clinical testing
GeneDx RCV000187858 SCV000241458 pathogenic not provided 2018-12-10 criteria provided, single submitter clinical testing The R201C missense change in the KCNQ2 gene has been reported as a de novo variant in multiple patients with neonatal encephalopathy previously tested at GeneDx and in the published literature (Weckhuysen et al., 2013; Mulkey et al., 2017). The R201C variant is not observed in large population cohorts (Lek et al., 2016). Functional studies suggest that the R201C variant results in gain-of-funtion (Miceli et al., 2015). The R201C variant is not observed in large population cohorts (Lek et al., 2016). The R201C variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution is predicted to be within the transmembrane segment S4 voltage sensor of the homologous domain. A different missense change at this residue (R201H) as well as missense variants in nearby residues have been reported in the Human Gene Mutation Database in individuals with KCNQ2-related disorders (Stenson et al., 2014). In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect.
GeneReviews RCV000203591 SCV000484565 pathogenic Early infantile epileptic encephalopathy 7 2016-03-31 no assertion criteria provided literature only EE (epileptic encephalopathy)
Invitae RCV000802499 SCV000942333 pathogenic Early infantile epileptic encephalopathy 2018-11-16 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 201 of the KCNQ2 protein (p.Arg201Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is not present in population databases (ExAC no frequency). This variant has been observed to be de novo in several individuals affected with early infantile epileptic encephalopathy (PMID: 24107868, 27535030, 28687180, 28133863). ClinVar contains an entry for this variant (Variation ID: 205869). Experimental studies have shown that this missense change stabilized the activated state of the channel, thereby producing gain-of function (PMID: 25740509). This variant disrupts the p.Arg210 amino acid residue in KCNQ2. Other variant(s) that disrupt this residue have been observed in affected individuals (PMID: 23708187, 25880994, 29190809, 28139826), suggesting that it is a clinically significant residue. As a result, variants that disrupt this residue are likely to be causative of disease. For these reasons, this variant has been classified as Pathogenic.
NeuroMeGen,Hospital Clinico Santiago de Compostela RCV000203591 SCV000258970 pathogenic Early infantile epileptic encephalopathy 7 criteria provided, single submitter clinical testing
SIB Swiss Institute of Bioinformatics RCV000203591 SCV000803440 pathogenic Early infantile epileptic encephalopathy 7 2018-05-31 criteria provided, single submitter curation This variant is interpreted as a Pathogenic, for Epileptic encephalopathy, early infantile, 7, in Autosomal Dominant manner. The following ACMG Tag(s) were applied: PP3 => Multiple lines of computational evidence support a deleterious effect on the gene or gene product. PS3 => Well-established functional studies show a deleterious effect. Loss of voltage-dependent channel gating and increased channel activation, gain-of-function mutation (PMID:25740509). PM2 => Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. PS4-Moderate => Recurrent mutation (PMID:26993267,28133863,24107868,28687180). PM6 => Assumed de novo, but without confirmation of paternity and maternity (PMID:28687180).

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