ClinVar Miner

Submissions for variant NM_001165963.4(SCN1A):c.5681T>C (p.Met1894Thr) (rs562208324)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000189015 SCV000242646 uncertain significance not provided 2017-01-27 criteria provided, single submitter clinical testing p.Met1894Thr (ATG>ACG): c.5681 T>C in exon 26 of the SCN1A gene (NM_001165963.1) A variant of uncertain significance has been identified in the SCN1A gene. The M1894T variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The M1894T variant is observed in 8/16512 (0.05%) alleles from individuals of South Asian background (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The M1894T 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. Additionally, this substitution alters a conserved position that is predicted to be within the C-terminal cytoplasmic domain, and in silico analysis predicts this variant is probably 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. The variant is found in EPILEPSY panel(s).
Mendelics RCV000986869 SCV001136014 uncertain significance Severe myoclonic epilepsy in infancy 2019-05-28 criteria provided, single submitter clinical testing
Invitae RCV001071764 SCV001237085 uncertain significance Early infantile epileptic encephalopathy 2019-10-18 criteria provided, single submitter clinical testing This sequence change replaces methionine with threonine at codon 1894 of the SCN1A protein (p.Met1894Thr). The methionine residue is highly conserved and there is a moderate physicochemical difference between methionine and threonine. This variant is present in population databases (rs562208324, ExAC 0.05%). This variant has not been reported in the literature in individuals with SCN1A-related conditions. ClinVar contains an entry for this variant (Variation ID: 206876). 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 disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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