ClinVar Miner

Submissions for variant NM_000238.3(KCNH2):c.3152+1G>T (rs1057518151)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000414266 SCV000491582 pathogenic not provided 2016-10-11 criteria provided, single submitter clinical testing Although the c.3152+1 G>T pathogenic variant in the KCNH2 gene has not been reported as a pathogenic variant or as a benign variant to our knowledge, it destroys the canonical splice donor site in intron 13 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. Other downstream splice site variants in the KCNH2 gene and a different pathogenic variant affecting the same nucleotide (c.3152+1 G>A) have been reported in HGMD in association with LQTS (Stenson et al., 2014). Furthermore, the c.3152+1 G>T variant was not observed in approximately 5,800 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project (average read depth 6X).In summary, c.3152+1 G>T in the KCNH2 gene is interpreted as a pathogenic variant.
Invitae RCV001378550 SCV001576138 likely pathogenic Long QT syndrome 2020-05-15 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 13 of the KCNH2 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate insufficient coverage at this position in the ExAC database. This variant has not been reported in the literature in individuals with KCNH2-related conditions. ClinVar contains an entry for this variant (Variation ID: 373026). 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 KCNH2 are known to be pathogenic (PMID: 10973849, 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.

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