ClinVar Miner

Submissions for variant NM_172107.3(KCNQ2):c.1067T>C (p.Leu356Pro) (rs1057518772)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000478321 SCV000571409 likely pathogenic not provided 2016-08-26 criteria provided, single submitter clinical testing The L356P 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, indicating it is not a common benign variant in these populations. The L356P variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution alters a conserved position in the cytoplasmic domain and in silico analysis predicts this variant is probably damaging to the protein structure/function. Furthermore, missense variants in the same residue (L356V) and many in nearby residues have been reported in the Human Gene Mutation Database in association with KCNQ2-related disorder (Stenson et al., 2014), supporting the functional importance of this region of the protein. Therefore, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded.
Invitae RCV000794694 SCV000934119 uncertain significance Early infantile epileptic encephalopathy 2018-12-05 criteria provided, single submitter clinical testing This sequence change replaces leucine with proline at codon 356 of the KCNQ2 protein (p.Leu356Pro). The leucine residue is highly conserved and there is a moderate physicochemical difference between leucine and proline. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with KCNQ2-related conditions. ClinVar contains an entry for this variant (Variation ID: 422045). 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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