ClinVar Miner

Submissions for variant NM_001040142.2(SCN2A):c.4121T>A (p.Met1374Lys) (rs555250264)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000414649 SCV000491949 uncertain significance not specified 2016-11-16 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the SCN2A gene. The M1374K variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. It was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project and and the 1000 Genomes Project reports M1347K was observed in 1/170 (0.56%) of alleles from individuals of Sierre Lione background. The M1374K 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 alters a position conserved in mammals predicted to be within the extracellular loop between the S5 and S6 transmembrane segments of the third homologous domain. 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.
Invitae RCV001063398 SCV001228241 uncertain significance Benign familial neonatal-infantile seizures; Early infantile epileptic encephalopathy 11 2019-12-12 criteria provided, single submitter clinical testing This sequence change replaces methionine with lysine at codon 1374 of the SCN2A protein (p.Met1374Lys). The methionine residue is highly conserved and there is a moderate physicochemical difference between methionine and lysine. This variant is present in population databases (rs555250264, ExAC 0.01%). This variant has not been reported in the literature in individuals with SCN2A-related conditions. ClinVar contains an entry for this variant (Variation ID: 373360). 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 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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