ClinVar Miner

Submissions for variant NM_172107.4(KCNQ2):c.583T>C (p.Ser195Pro) (rs796052620)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000187855 SCV000241455 pathogenic not provided 2012-09-17 criteria provided, single submitter clinical testing p.Ser195Pro (TCT>CCT):c.583 T>C in exon 4 of the KCNQ2 gene (NM_172107.2)The Ser195Pro missense change has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The NHLBI ESP Exome Variant Project has not identified Ser195Pro 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 polar Serine is replaced by a non-polar Proline, and the gain of a bulky Proline residue may alter the secondary structure of the protein. Ser195Pro alters a highly conserved position in the linker region between the S3 and S4 transmembrane segments of the protein. Some in silico algorithms predict Ser195Pro may be damaging to protein structure/function, although one model suggests it is benign. Therefore, based on the currently available information, it is unclear whether Ser195Pro is a disease-causing mutation or a rare benign variant. The variant is found in INFANT-EPI panel(s).
Invitae RCV000808224 SCV000948320 likely pathogenic Early infantile epileptic encephalopathy 2019-02-13 criteria provided, single submitter clinical testing This sequence change replaces serine with proline at codon 195 of the KCNQ2 protein (p.Ser195Pro). The serine residue is highly conserved and there is a moderate physicochemical difference between serine and proline. This variant is not present in population databases (ExAC no frequency). This variant has been observed in an individual affected with early infantile epileptic encephalopathy (EIEE) (PMID: 24107868) and has been observed to be de novo in an individual affected with EIEE (Invitae). ClinVar contains an entry for this variant (Variation ID: 205866). 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. For these reasons, this allele has been classified as Likely Pathogenic.
GeneReviews RCV000678127 SCV000484563 pathogenic Early infantile epileptic encephalopathy 7 2016-03-31 no assertion criteria provided literature only Infantile spasms

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