ClinVar Miner

Submissions for variant NM_014191.4(SCN8A):c.4423G>A (p.Gly1475Arg) (rs796053216)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Center of Genomic medicine, Geneva,University Hospital of Geneva RCV000627041 SCV000747746 likely pathogenic Epilepsy 2017-11-06 criteria provided, single submitter clinical testing This variant was identified in a mosaic state in a young female patient with epilepsy.
GeneDx RCV000189277 SCV000242909 pathogenic not provided 2017-02-14 criteria provided, single submitter clinical testing The c.4423 G>A variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. It was not observed in approximately 6,200 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Multiple in silico algorithms predict that c.4423 G>A may create a cryptic splice acceptor site in exon 25; however, in the absence of RNA/functional studies the actual effect of c.4423 G>A on splicing is unknown. If c.4423 G>A does not alter splicing, it will result in the G1475R missense change, which is a non-conservative amino acid substitution that is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. G1475R alters a conserved position in the cytoplasmic loop between the 3rd and 4th homologous domains. However, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function.
Genetic Services Laboratory, University of Chicago RCV000500598 SCV000596983 likely pathogenic Early infantile epileptic encephalopathy 13 2015-10-29 criteria provided, single submitter clinical testing
Invitae RCV000462091 SCV000544813 likely pathogenic Early infantile epileptic encephalopathy 2018-04-09 criteria provided, single submitter clinical testing This sequence change replaces glycine with arginine at codon 1475 of the SCN8A protein (p.Gly1475Arg). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and arginine. This variant is not present in population databases (ExAC no frequency). This variant has been reported to be de novo in an individual affected with early infantile epileptic encephalopathy (PMID: 27864847). ClinVar contains an entry for this variant (Variation ID: 207119). 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: "Benign"; Align-GVGD: "Class C0"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Neurogenetics Laboratory - MEYER,AOU Meyer RCV000416962 SCV000494529 likely pathogenic Epileptic encephalopathy 2016-11-16 criteria provided, single submitter clinical testing

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