ClinVar Miner

Submissions for variant NM_181798.1(KCNQ1):c.1321G>C (p.Gly441Arg) (rs199472807)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000691158 SCV000818903 likely pathogenic Long QT syndrome 2018-03-08 criteria provided, single submitter clinical testing This sequence change replaces glycine with arginine at codon 568 of the KCNQ1 protein (p.Gly568Arg). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and arginine. This variant is not present in population databases (ExAC no frequency). This variant has been reported to segregate with long QT syndrome in a family and has been reported in individuals with this condition (PMID: 23392653, 22456477). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). Other missense substitutions at this codon (p.Gly568Glu and p.Gly568Ala) have been reported in individuals affected with long QT syndrome (PMID: 27041096, 12702160). A different variant (c.1702G>A) giving rise to the same protein effect observed here (p.Gly568Arg) has been reported in an individual affected with long QT syndrome (PMID: 22956155). This suggests that the glycine residue is critical for KCNQ1 protein function. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

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