ClinVar Miner

Submissions for variant NM_001165963.4(SCN1A):c.5567T>C (p.Met1856Thr) (rs796053041)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000189008 SCV000242639 pathogenic not provided 2012-10-04 criteria provided, single submitter clinical testing p.Met1856Thr (ATG>ACG):c.5567 T>C in exon 26 of the SCN1A gene (NM_001165963.1) The Met1856Thr missense change was previously identified in a proband with febrile seizures plus (FS+), although no additional information was provided to unequivocally demonstrate that it is pathogenic (Hattori et al., 2008). The NHLBI ESP Exome Variant Project has not identified Met1856Thr in approximately 6,500 individuals of European or African American ethnicity, indicating that it is not a common benign variant in these populations. The amino acid substitution is non-conservative, as a non-polar Methionine residue is replaced by a polar Threonine residue. Met1856Thr alters a position in the C-terminal region that is highly conserved across species and in related proteins, and multiple pathogenic mutations at neighboring residues have been reported in this region. Multiple in silico algorithms predict Met1856Thr is damaging to protein structure/function, although another model suggests it may be benign. This variant has been observed de novo with confirmed parentage. The variant is found in INFANT-EPI panel(s).
Invitae RCV001067049 SCV001232081 uncertain significance Early infantile epileptic encephalopathy 2019-08-27 criteria provided, single submitter clinical testing This sequence change replaces methionine with threonine at codon 1856 of the SCN1A protein (p.Met1856Thr). The methionine residue is highly conserved and there is a moderate physicochemical difference between methionine and threonine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals with febrile seizures plus (PMID: 18076640, 29655203). ClinVar contains an entry for this variant (Variation ID: 206870). 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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