ClinVar Miner

Submissions for variant NM_172056.2(KCNH2):c.2399G>C (p.Gly800Ala) (rs794728391)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000181858 SCV000234161 pathogenic not provided 2018-06-22 criteria provided, single submitter clinical testing The c.2398+1 G>C pathogenic variant in the KCNH2 gene has been reported in association with LQTS (Curran et al., 1995; Tester et al., 2005). This variant destroys the canonical splice donor site in intron 9 and is predicted to cause abnormal gene splicing. Functional studies indicate that the c.2398+1 G>C variant activates a cryptic splice site and generates a full-length hERG protein with an insertion of 18 amino acids in the middle of the cyclic nucleotide binding domain; the mutant channel displays a trafficking defect and causes dominant negative suppression of wild-type channel function by intracellular retention of heteromeric channels (Gong et al., 2008). Other splice site variants in the KCNH2 gene, including a variant at the same nucleotide position (c.2398+1 G>T) have been reported in HGMD in association with LQTS (Stenson et al., 2014). Furthermore, the c.2398+1 G>C variant is not observed in large population cohorts (Lek et al., 2016).
OMIM RCV000015503 SCV000035768 pathogenic Long QT syndrome 2 1995-03-10 no assertion criteria provided literature only

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