ClinVar Miner

Submissions for variant NM_172056.2(KCNH2):c.2145+1G>A (rs886039385)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000255301 SCV000321766 pathogenic not provided 2016-08-04 criteria provided, single submitter clinical testing Although the c.2145+1 G>A variant has not been reported as a pathogenic variant or as a benign variant to our knowledge, it has been previously observed in one other unrelated individual referred for LQTS genetic testing at GeneDx. This variant destroys the canonical splice donor site in intron 8 and is predicted to cause abnormal gene splicing. This variant is predicted to lead to either an abnormal message that is subject to nonsense-mediated mRNA decay, or to an abnormal protein product if the message is used for protein translation. Multiple other downstream splice site variants in the KCNH2 gene have been reported in HGMD in association with LQTS (Stenson et al., 2014). Furthermore, the c.2145+1 G>A variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. In summary, c.2145+1 G>A in the KCNH2 gene is expected to be pathogenic.
Invitae RCV000477020 SCV000543421 likely pathogenic Long QT syndrome 2016-04-23 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 8 of the KCNH2 gene. It is expected to disrupt mRNA splicing and likely results in an absent or disrupted protein product. This variant has not been reported in the literature in individuals with a KCNH2-related disease. In summary, donor and acceptor splice site variants are typically truncating (PMID: 16199547), and truncating variants in KCNH2 are known to be pathogenic (PMID: 19862833). However, without additional functional and/or genetic data, this variant has been classified as Likely Pathogenic.

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