ClinVar Miner

Submissions for variant NM_172107.3(KCNQ2):c.593G>A (p.Arg198Gln) (rs796052621)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000623027 SCV000741547 pathogenic Inborn genetic diseases 2016-06-13 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: LIKELY POSITIVE: Relevant Alteration(s) Detected
CeGaT Praxis fuer Humangenetik Tuebingen RCV000187856 SCV000575319 uncertain significance not provided 2016-09-30 criteria provided, single submitter clinical testing
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago RCV000768251 SCV000898777 pathogenic Benign familial neonatal seizures 1; Early infantile epileptic encephalopathy 7 2018-05-30 criteria provided, single submitter clinical testing KCNQ2 NM_172107.3 exon 4 p.Arg198Gln (c.593G>A): This variant has been reported in the literature as de novo in at least 4 individuals with infantile spasms and hypsarrhythmia (Millichap 2017 PMID:27861786). This variant is not present in large control databases. This variant is present in ClinVar (Variation ID:205867). Evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. Of note, splice prediction tools strongly predict the creation of a new acceptor site; however, further studies are needed to understand its impact. Functional studies also support this variant may impact the protein, potentially creating a gain of function (Millichap 2017 PMID:27861786). In summary, this variant is classified as pathogenic.
GeneDx RCV000187856 SCV000241456 pathogenic not provided 2015-10-28 criteria provided, single submitter clinical testing p.Arg198Gln (CGG>CAG): c.593 G>A in exon 4 in the KCNQ2 gene (NM_172107.2) R198Q missense change was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. R198Q is a non-conservative amino acid substitution as a positively charged Arginine residue is replaced by an uncharged Glutamine residue. It alters a highly conserved position in the S4 (voltage-sensor) segment of the KCNQ2 protein, and functional studies predict that the R198Q substitution alters voltage gating of the channel (Miceli et al., 2008). Additionally, multiple in silico algorithms predict R198Q may be damaging to protein structure/function. Therefore, based on the currently available information, R198Q is a strong candidate for a disease-causing mutation, although the possibility that it is a benign variant cannot be excluded. The variant is found in INFANT-EPI,EPILEPSY panel(s).
Invitae RCV000807499 SCV000947555 pathogenic Early infantile epileptic encephalopathy 2018-09-17 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 198 of the KCNQ2 protein (p.Arg198Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. 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-onset epilepsy in infancy (PMID: 27861786, 29390993). ClinVar contains an entry for this variant (Variation ID: 205867). Experimental studies have shown that this missense change activates channels at less depolarizing potentials, and suggesting a gain-of-function effect (PMID: 27861786). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. For these reasons, this variant has been classified as Pathogenic.

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