ClinVar Miner

Submissions for variant NM_172107.4(KCNQ2):c.998G>A (p.Arg333Gln) (rs118192216)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000413623 SCV000491166 likely pathogenic not provided 2016-02-24 criteria provided, single submitter clinical testing The R333Q variant has been reported previously in association with benign familial neonatal seizures (BFNS) (Singh et al., 2003). Functional studies indicate that R333Q moderately reduces channel function (Singh et al., 2003). It 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. The R333Q variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. Additionally, this substitution occurs at a position that is conserved across species. Furthermore, missense variants at the same position (R333W) and in nearby residues (H324R, R325G, A337G, L339R) have been reported in the Human Gene Mutation Database in association with KCNQ2-related disorders (Stenson et al., 2014), supporting the functional importance of this region of the protein. However, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded.
Invitae RCV000813877 SCV000954258 pathogenic Early infantile epileptic encephalopathy 2019-12-03 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 333 of the KCNQ2 protein (p.Arg333Gln). 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 individual(s) with infantile seizures (PMID: 14534157, 29215089, Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 21810). This variant has been reported to affect KCNQ2 protein function (PMID: 14534157, 30126342). This variant disrupts the p.Arg333 amino acid residue in KCNQ2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 23621294, 23692823, 16039833). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
GeneReviews RCV000678102 SCV000041668 pathogenic Benign familial neonatal seizures 1 2016-03-31 no assertion criteria provided literature only BFNE (benign familial neonatal epilepsy)

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