ClinVar Miner

Submissions for variant NM_172057.2(KCNH2):c.73C>T (p.Arg25Trp)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000818387 SCV000958997 uncertain significance Long QT syndrome 2018-11-05 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 25 of the KCNH2 protein (p.Gly25Trp). The arginine residue is weakly conserved and there is a moderate physicochemical difference between arginine and tryptophan. The KCNH2 gene has multiple clinically relevant transcripts. The p.Gly25Trp variant occurs in alternate transcript NM_172057.2, which corresponds to position c.1128+1860C>T in NM_000238.3, the primary transcript listed in the Methods. This variant is present in population databases (rs767264288, ExAC 0.02%). This variant has been observed in an intrauterine fetal death (PMID: 23571586) and in combination with a variant in SCN5A in a family with Brugada syndrome (PMID: 25626866). Experimental studies have shown that this missense change affects protein stability and trafficking, resulting in reduced channel current density (PMID: 23571586, 26772437). 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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