ClinVar Miner

Submissions for variant NM_181798.1(KCNQ1):c.302+1G>A (rs1589957233)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000806826 SCV000946845 likely pathogenic Long QT syndrome 2018-08-20 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 4 of the KCNQ1 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). Disruption of this splice site has been observed in an individual affected with long QT syndrome (PMID: 26132555). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in KCNQ1 are known to be pathogenic (PMID: 9323054, 19862833). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000825588 SCV000966930 likely pathogenic Congenital long QT syndrome 2017-09-08 criteria provided, single submitter clinical testing The c.683+1G>A variant in KCNQ1 has not been previously reported in individuals with long QT syndrome or in large population studies. This variant occurs in the invariant region (+/- 1,2) of the splice consensus sequence and is predicted to cause altered splicing leading to an abnormal or absent protein. Loss-of-functi on variants in KCNQ1 are associated with LQTS (also known as Romano-Ward syndrom e) in the heterozygous state and with Jervell and Lange-Nielsen syndrome (JLNS) in the compound heterozygous or homozygous state. In summary, although additiona l studies are required to fully establish its clinical significance, the c.683+1 G>A variant is likely pathogenic. ACMG/AMP criteria applied: PVS1, PM2.

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