ClinVar Miner

Submissions for variant NM_020822.3(KCNT1):c.1928G>A (p.Arg643Gln) (rs141281093)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000717701 SCV000848559 likely benign Seizures 2016-12-20 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Subpopulation frequency in support of benign classification,In silico models in agreement (benign)
CeGaT Praxis fuer Humangenetik Tuebingen RCV000659136 SCV000780951 uncertain significance not provided 2018-03-31 criteria provided, single submitter clinical testing
GeneDx RCV000441744 SCV000527832 likely benign not specified 2016-05-20 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Invitae RCV000650641 SCV000772488 uncertain significance Early infantile epileptic encephalopathy 14; Epilepsy, nocturnal frontal lobe, 5 2018-01-30 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 643 of the KCNT1 protein (p.Arg643Gln). The arginine residue is weakly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs141281093, ExAC 0.05%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has not been reported in the literature in individuals with KCNT1-related disease. ClinVar contains an entry for this variant (Variation ID: 386260). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The glutamine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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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