ClinVar Miner

Submissions for variant NM_000238.4(KCNH2):c.76+2T>A

dbSNP: rs794728419
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Institute of Human Genetics, University of Goettingen RCV001802757 SCV002047688 likely pathogenic Long QT syndrome 2 2022-01-04 criteria provided, single submitter clinical testing The variant c.76+2T>A (p.?) is located in the donor splice site of intron 1 of the KCNH2-gene, it affects a canonical splice site and it is not found in the gnomAD database. In silico programs predict a significant impact on KCNH2-RNA splicing (varSEAK SSP, SpliceSiteFinder-like, MaxEntScan, NNSPLICE and GeneSplicer), which has not been validated by functional studies yet. This variant was found in a patient, who was referred to our institute due to the clinical diagnosis of a Long QT syndrome. ACMG criteria used for classification: PVS1, PM2.
Labcorp Genetics (formerly Invitae), Labcorp RCV002541373 SCV003320562 likely pathogenic Long QT syndrome 2022-03-01 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 1 of the KCNH2 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in KCNH2 are known to be pathogenic (PMID: 10973849, 19862833). This variant is not present in population databases (gnomAD no frequency). 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 1331098). Disruption of this splice site has been observed in individual(s) with long QT syndrome (PMID: 23631430; Invitae).

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