ClinVar Miner

Submissions for variant NM_001165963.4(SCN1A):c.4219C>T (p.Arg1407Ter) (rs398123593)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000079581 SCV000111463 pathogenic not provided 2013-05-09 criteria provided, single submitter clinical testing
Invitae RCV000636415 SCV000757854 pathogenic Early infantile epileptic encephalopathy 2019-11-04 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Arg1407*) in the SCN1A gene. It is expected to result in an absent or disrupted protein product. 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 severe myoclonic epilepsy in infancy (PMID: 11940708). It has also been found in an individual with atypical Dravet syndrome (PMID: 24502503). This variant is also known as 4186C>T and Arg1396X in the literature. ClinVar contains an entry for this variant (Variation ID: 93649). Loss-of-function variants in SCN1A are known to be pathogenic (PMID: 17347258, 18930999). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV000720923 SCV000851807 pathogenic History of neurodevelopmental disorder 2016-06-08 criteria provided, single submitter clinical testing Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation;Confirmed de novo alteration in the setting of a new disease (appropriate phenotype) in the family;Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)
GeneDx RCV000079581 SCV000890253 pathogenic not provided 2018-12-12 criteria provided, single submitter clinical testing The R1407X nonsense variant in the SCN1A gene has been reported previously as a de novo variant in multiple unrelated individuals with SCN1A-related disorders (Sugawara et al., 2002; Berkovic et al., 2006; Kearney et al., 2006). Due to use of alternative nomenclature, this variant has been reported as R1396X (Sugawara et al., 2002). Functional studies suggest that R1407X results in loss-of-function (Ogiwara et al., 2007; Kim et al., 2018). This pathogenic variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The R1407X variant is not observed in large population cohorts (Lek et al., 2016).

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