ClinVar Miner

Submissions for variant NM_172107.4(KCNQ2):c.620G>A (p.Arg207Gln) (rs118192200)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000187863 SCV000241463 pathogenic not provided 2018-03-05 criteria provided, single submitter clinical testing The R207Q variant has been previously reported in an individual with myokymia due to peripheral nerve hyperexcitability, and functional studies indicate this variant alters voltage-dependent activation (Wuttke et al., 2007; Miceli et al., 2012). Additionally, a different missense substitution at the same position (R207W) has been previously reported in unrelated families with neonatal seizures (Dedek et al., 2001; Blumkin et al., 2012). The R207Q variant is not observed in large population cohorts (Lek et al., 2016). The R207Q variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution is predicted to be within the transmembrane segment S4 voltage sensor. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Therefore, we interpret R207Q as a pathogenic variant, and its presence is consistent with the diagnosis of a KCNQ2-related disorder in this individual.
Fulgent Genetics,Fulgent Genetics RCV000763453 SCV000894229 pathogenic Benign familial neonatal seizures 1; Early infantile epileptic encephalopathy 7 2018-10-31 criteria provided, single submitter clinical testing
Athena Diagnostics Inc RCV000187863 SCV001144319 pathogenic not provided 2019-01-08 criteria provided, single submitter clinical testing Not found in the total gnomAD dataset, and the data is high quality (0/270462 chr). Predicted to have a damaging effect on the protein. One de novo case with parental identity confirmed.
Invitae RCV001205287 SCV001376533 likely pathogenic Early infantile epileptic encephalopathy 2019-08-28 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 207 of the KCNQ2 protein (p.Arg207Gln). 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 in several individuals affected with KCNQ2-related conditions (PMID: 29655203, 25959266, 17872363). ClinVar contains an entry for this variant (Variation ID: 7391). This variant has been reported to affect KCNQ2 protein function (PMID: 22455920, 17872363). 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. This variant disrupts the p.Arg207 amino acid residue in KCNQ2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11572947, 24375629, 22169383). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
OMIM RCV000007815 SCV000028020 pathogenic Seizures, benign familial neonatal, 1, and/or myokymia 2007-11-27 no assertion criteria provided literature only
GeneReviews RCV000678085 SCV000041646 pathogenic Early infantile epileptic encephalopathy 7 2016-03-31 no assertion criteria provided literature only Myokymia, EE (epileptic encephalopathy)

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