ClinVar Miner

Submissions for variant NM_020822.3(KCNT1):c.1421G>A (p.Arg474His) (rs397515404)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000624507 SCV000741205 pathogenic Inborn genetic diseases 2015-11-20 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: POSITIVE: Relevant Alteration(s) Detected
Baylor Miraca Genetics Laboratories, RCV000032795 SCV000807326 pathogenic Early infantile epileptic encephalopathy 14 2017-09-01 criteria provided, single submitter clinical testing This mutation has been previously reported as disease-causing and was found once in our laboratory de novo in a 11-year-old male with infantile-onset epilepsy, neurodevelopmental delay, lack of social interaction, myopia, strabismus
GeneDx RCV000414268 SCV000490584 pathogenic not provided 2016-11-14 criteria provided, single submitter clinical testing The R474H missense variant in the KCNT1 gene has been reported previously as a de novo pathogenic variant in individuals with malignant migrating partial seizures of infancy (MMPSI) and West syndrome (Lee et al., 2014; Barcia et al., 2012; Ohba et al., 2015). A different missense variant at the same position (R474C) has been reported as a pathogenic variant in individuals with epilepsy of infancy with migrating focal seizures (EIFMS) (Ohba et al., 2015; Shimada et al., 2014). The R474H 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. This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function.
Invitae RCV000546032 SCV000652908 pathogenic Early infantile epileptic encephalopathy 14; Epilepsy, nocturnal frontal lobe, 5 2018-11-06 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 474 of the KCNT1 protein (p.Arg474His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is not present in population databases (rs397515404, ExAC no frequency). This variant has been shown to arise de novo in several individuals affected with malignant migrating partial seizures of infancy, and early onset epileptic encephalopathies (PMID: 23086397, 26140313, 25326637) and in individuals affected with autosomal dominant nocturnal frontal lobe epilepsy, and migrating focal seizure of infancy (PMID: 25482562, 26740507). This variant is also known as c.1286G>A:p.R429H in the literature. ClinVar contains an entry for this variant (Variation ID: 39595). A different missense substitution at this codon (p.R474C) has been determined to be pathogenic (PMID: 26140313, 27652284). This suggests that the arginine residue is critical for KCNT1 protein function and that other missense substitutions at this position may also be pathogenic. For these reasons, this variant has been classified as Pathogenic.
Laboratory of Medical Genetics,National & Kapodistrian University of Athens RCV000032795 SCV000928394 likely pathogenic Early infantile epileptic encephalopathy 14 2018-12-03 criteria provided, single submitter clinical testing PS3, PM2, PM5, PP3
OMIM RCV000032795 SCV000056563 pathogenic Early infantile epileptic encephalopathy 14 2012-11-01 no assertion criteria provided literature only
UCLA Clinical Genomics Center, UCLA RCV000032795 SCV000255509 pathogenic Early infantile epileptic encephalopathy 14 2014-02-04 criteria provided, single submitter clinical testing

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