ClinVar Miner

Submissions for variant NM_000238.4(KCNH2):c.2399-28del

dbSNP: rs2116941701
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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Kids Neuroscience Centre, Sydney Children's Hospitals Network RCV001726510 SCV001571526 pathogenic Long QT syndrome 2 criteria provided, single submitter clinical testing mRNA studies establish the KCNH2 c.2399-28delA variant leads to loss of the long isoforms of KCNH2 from t paternal allele in blood RNA. The mechanism for mis-splicing is likely due to loss of the only available branchpoint adenosine for intron branching, which is required for excision of the intron-9 lariat and ligation of exon 9 and exon 10. There are several pathogenic variants associated with Long QT syndrome reported in Clinvar in exons 10-15 of KCNH2 that affect only the long isoforms of KCNH2. And, loss-of-function variants are a known pathogenetic mechanism in Long QT syndrome. Therefore, haploinsufficiency of long isoforms of KCNH2 due to the c.239928del variant is consistent with the known pathogenetic mechanism in Long QT syndrome.

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