ClinVar Miner

Submissions for variant NM_004974.4(KCNA2):c.1118C>T (p.Thr373Ile) (rs1553181282)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000520764 SCV000621412 likely pathogenic not provided 2017-10-04 criteria provided, single submitter clinical testing The T373I variant in the KCNA2 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. It was identified as a de novo variant with confirmed parentage in a patient with a neurodevelopmental disorder previously tested at GeneDx. It is not observed in large population cohorts (Lek et al., 2016). The T373I variant is a non-conservative amino acid substitution that occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret T373I as a likely pathogenic variant.
Mendelics RCV000986393 SCV001135389 likely pathogenic Epileptic encephalopathy, early infantile, 32 2019-05-28 criteria provided, single submitter clinical testing
Invitae RCV000986393 SCV001221242 uncertain significance Epileptic encephalopathy, early infantile, 32 2019-12-30 criteria provided, single submitter clinical testing This sequence change replaces threonine with isoleucine at codon 373 of the KCNA2 protein (p.Thr373Ile). The threonine residue is highly conserved and there is a moderate physicochemical difference between threonine and isoleucine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with KCNA2-related conditions. ClinVar contains an entry for this variant (Variation ID: 452594). 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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