ClinVar Miner

Submissions for variant NM_006920.6(SCN1A):c.3866C>T (p.Thr1289Ile) (rs146878122)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000717317 SCV000848167 likely benign History of neurodevelopmental disorder 2017-01-06 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)
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000724898 SCV000332268 uncertain significance not provided 2015-06-16 criteria provided, single submitter clinical testing
GeneDx RCV000724898 SCV000242564 uncertain significance not provided 2018-04-16 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the SCN1A gene. The T1300I variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The T1300I variant is observed in 7/11318 (0.06%) alleles from individuals of Latino background (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The T1300I variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved in mammals and is predicted to be within the transmembrane segment S3 of the third homologous domain. A different amino acid substitution at this position (T1300R) has been reported previously in association with Dravet syndrome, although information about parental testing was not provided (Xu et al., 2014). In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Genetic Services Laboratory, University of Chicago RCV000188933 SCV000596951 uncertain significance not specified 2017-05-02 criteria provided, single submitter clinical testing
Invitae RCV000471568 SCV000548773 uncertain significance Early infantile epileptic encephalopathy 2018-12-18 criteria provided, single submitter clinical testing This sequence change replaces threonine with isoleucine at codon 1300 of the SCN1A protein (p.Thr1300Ile). The threonine residue is highly conserved and there is a moderate physicochemical difference between threonine and isoleucine. This variant is present in population databases (rs146878122, ExAC 0.06%) but has not been reported in the literature in individuals with a SCN1A-related disease. ClinVar contains an entry for this variant (Variation ID: 206812). This variant identified in the SCN1A gene is located in the transmembrane spanning D3-S3 region of the resulting protein (PMID: 25348405, 18804930), but it is unclear how this variant impacts the function of this protein. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies. In summary, this variant is a rare missense change that is not predicted to affect protein function, and is found in the population at an appreciable frequency. This variant is not anticipated to cause disease; however, the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.

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