ClinVar Miner

Submissions for variant NM_172107.4(KCNQ2):c.1639C>T (p.Arg547Trp) (rs796052650)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000187911 SCV000241513 likely pathogenic not provided 2018-09-19 criteria provided, single submitter clinical testing The R547W variant has been previously reported in two related individuals with benign familial neonatal seizures (Zara et al., 2013). 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 R547W 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 occurs at a position where amino acids with similar properties to Arginine are tolerated across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. therefore, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded.
Center for Pediatric Genomic Medicine,Children's Mercy Hospital and Clinics RCV000187911 SCV000511083 likely pathogenic not provided 2016-09-02 criteria provided, single submitter clinical testing
Invitae RCV000551309 SCV000634050 uncertain significance Early infantile epileptic encephalopathy 2019-11-24 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 547 of the KCNQ2 protein (p.Arg547Trp). The arginine residue is moderately conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is not present in population databases (rs796052650, ExAC no frequency). This variant has been reported to segregate with benign familial neonatal seizures in a single family and has also been observed in an individual affected with epilepsy and neurodevelopmental disorders (PMID: 23360469, 29655203). ClinVar contains an entry for this variant (Variation ID: 205912). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, this variant is a rare missense change with uncertain impact on protein function. While it is absent from the population and reported in affected individuals, the available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000187911 SCV001247376 pathogenic not provided 2017-11-01 criteria provided, single submitter clinical testing
GeneReviews RCV000678183 SCV000484630 pathogenic Benign familial neonatal seizures 1 2016-03-31 no assertion criteria provided literature only BFNE (benign familial neonatal epilepsy)

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