Submissions for variant NM_172056.2(KCNH2):c.77-1G>A (rs794728406)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000181919	SCV000234222	likely pathogenic	not provided	2016-08-19	criteria provided, single submitter	clinical testing	the c.77-1 G>A variant has not been reported as a pathogenic variant or as a benign variant to our knowledge. However, this variant has been identified in conjunction with an additional cardiogenetic variant in one individual referred for LQTS genetic testing at GeneDx. So far, segregation data is limited or absent for this individual due to the lack of clinical information provided and/or insufficient participation by informative family members. The c.77-1 G>A variant destroys the canonical splice acceptor site in intron 1 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 splice site variants in the KCNH2 gene have been reported in HGMD in association with LQTS (Stenson et al., 2014). Furthermore, the c.77-1 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.
Invitae	RCV001379136	SCV001576877	likely pathogenic	Long QT syndrome	2020-03-31	criteria provided, single submitter	clinical testing	This sequence change affects an acceptor splice site in intron 1 of the KCNH2 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). This variant has been observed in individual(s) with clinical features of long QT syndrome (Invitae). ClinVar contains an entry for this variant (Variation ID: 200537). 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.