ClinVar Miner

Submissions for variant NM_172107.4(KCNQ2):c.1057C>T (p.Arg353Cys) (rs118192218)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000187895 SCV000241497 likely pathogenic not provided 2016-08-26 criteria provided, single submitter clinical testing The presence of the Arg353Cys variant previously identified in an research laboratory was confirmed in the submitted specimen. The Arg353Cys missense change has not been previously reported as a mutation or a benign polymorphism to our knowledge. A different amino acid substitution at the same position (Arg353Gly) has been previously reported in a family with benign familial neonatal seizures (Richards et al., 2004). Additionally, functional studies demonstrated that Arg353Gly alters the structure of the C-terminal region and disrupts the calmodulin binding domain of KCNQ2. This mutation was predicted to disrupt the KCNQ2 channel function and neuronal excitability (Richards et al., 2004). The Arg353Cys 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. It alters a position in the protein that is highly conserved across species. In silico analysis predicts Arg353Cys likely has a damaging effect on protein/structure and function. Therefore, based on currently available information GeneDx interprets Arg353Cys as a variant, likely mutation.
Athena Diagnostics Inc RCV000517065 SCV000613874 uncertain significance not specified 2016-09-29 criteria provided, single submitter clinical testing
Invitae RCV000694219 SCV000822653 uncertain significance Early infantile epileptic encephalopathy 2018-06-11 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 353 of the KCNQ2 protein (p.Arg353Cys). 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 not been reported in the literature in individuals with KCNQ2-related disease. ClinVar contains an entry for this variant (Variation ID: 205898). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C15"). The observation of one or more missense substitutions at this codon (p.R353G and p.R353H) in affected individuals suggests that this may be a clinically significant residue (PMID: 14985406, 26007637). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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