ClinVar Miner

Submissions for variant NM_172056.2(KCNH2):c.663C>G (p.His221Gln)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000802514 SCV000942349 uncertain significance Long QT syndrome 2018-10-29 criteria provided, single submitter clinical testing This sequence change replaces histidine with glutamine at codon 221 of the KCNH2 protein (p.His221Gln). The histidine residue is weakly conserved and there is a small physicochemical difference between histidine and glutamine. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate insufficient coverage at this position in the ExAC database. This missense change has been observed in an individual who suffered a sudden unexplained death (PMID: 29247119). 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 tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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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