ClinVar Miner

Submissions for variant NM_001330260.2(SCN8A):c.5280G>A (p.Met1760Ile)

dbSNP: rs1555231013
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
CeGaT Center for Human Genetics Tuebingen RCV000512684 SCV000608649 uncertain significance not provided 2017-03-01 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV001201742 SCV001372828 pathogenic Early infantile epileptic encephalopathy with suppression bursts 2019-07-29 criteria provided, single submitter clinical testing This sequence change replaces methionine with isoleucine at codon 1760 of the SCN8A protein (p.Met1760Ile). The methionine residue is highly conserved and there is a small physicochemical difference between methionine and isoleucine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals(s) affected with SCN8A-related epileptic encephalopathy (PMID: 30615093, Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 444294). This variant has been reported to affect SCN8A protein function (PMID:30615093). For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV000512684 SCV005327755 pathogenic not provided 2024-01-03 criteria provided, single submitter clinical testing Published functional studies demonstrate a damaging effect and show that this variant produces a hyperpolarizing shift in the activation curve of the channel and delays the transition to fast inactivation supporting a gain-of-function effect (PMID: 30615093); Not observed at significant frequency in large population cohorts (gnomAD); Missense variants in this gene are a common cause of disease and they are underrepresented in the general population; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This substitution is predicted to be within the transmembrane segment S6 of the fourth homologous domain; This variant is associated with the following publications: (PMID: 30615093)

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