ClinVar Miner

Submissions for variant NM_001040142.2(SCN2A):c.1399G>A (p.Ala467Thr) (rs745774658)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000522032 SCV000621281 uncertain significance not provided 2017-10-04 criteria provided, single submitter clinical testing The A467T variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The A467T variant is observed in 7/34410 (0.02%) alleles from individuals of Latino background (Lek et al., 2016). The A467T 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; however, Threonine is observed at this position in evolution. 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.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000522032 SCV001152478 uncertain significance not provided 2016-08-01 criteria provided, single submitter clinical testing
Invitae RCV001214677 SCV001386371 uncertain significance Benign familial neonatal-infantile seizures; Early infantile epileptic encephalopathy 11 2019-05-07 criteria provided, single submitter clinical testing This sequence change replaces alanine with threonine at codon 467 of the SCN2A protein (p.Ala467Thr). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and threonine. This variant is present in population databases (rs745774658, ExAC 0.02%). This variant has not been reported in the literature in individuals with SCN2A-related conditions. ClinVar contains an entry for this variant (Variation ID: 452471). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The threonine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. 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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