ClinVar Miner

Submissions for variant NM_172056.2(KCNH2):c.1945+6T>C (rs794728380)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000181831 SCV000234134 pathogenic not provided 2017-04-28 criteria provided, single submitter clinical testing The c.1945+6 T>C variant has been reported in a large family with LQTS, and it was absent from 320 control individuals (Zhang L et al., 2004). Zhang et al. identified c.1945+6 T>C in multiple affected individuals from one family and determined it co-segregated with disease across multiple generations. Functional studies suggest the intron is retained, which renders the protein non-functional and disrupts channel function (De Conti et al., 2012). Other splice site variants in the KCNH2 gene have been reported in association with LQTS.
Invitae RCV000227185 SCV000283968 pathogenic Long QT syndrome 2018-02-25 criteria provided, single submitter clinical testing This sequence change falls in intron 7 of the KCNH2 mRNA. It does not directly change the encoded amino acid sequence of the KCNH2 protein. This variant is not present in population databases (ExAC no frequency). This variant was shown to segregated with Long QT syndrome is a large multigenerational family (PMID: 15364333). ClinVar contains an entry for this variant (Variation ID: 200400). In experimental studies this variant was shown to affect KCNH2 protein splicing and result in intronic retention (PMID: 15364333, 22617876). In summary, this is a rare variant which segregates with disease and affects KCNH2 protein function, for these reasons it has been classified as Pathogenic.

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