Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV000703830 | SCV000832751 | pathogenic | Long QT syndrome | 2024-02-29 | criteria provided, single submitter | clinical testing | This sequence change falls in intron 9 of the KCNH2 gene. It does not directly change the encoded amino acid sequence of the KCNH2 protein. It affects a nucleotide within the consensus splice site. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individuals with long QT syndrome (PMID: 19841300). ClinVar contains an entry for this variant (Variation ID: 200446). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV000703830 | SCV001478567 | likely pathogenic | Long QT syndrome | 2021-01-07 | criteria provided, single submitter | clinical testing | Variant summary: KCNH2 c.2398+5G>T alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Four predict that the variant weakens or abolishes a canonical 5-prime donor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 250960 control chromosomes. c.2398+5G>T has been reported in the literature in individuals affected with Long QT Syndrome (e.g. Tester_2005, Kapplinger_2009) and in individual with sudden unexpected death (Tester_2012) . These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and cited the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. |
| Ambry Genetics | RCV003298232 | SCV003997359 | likely pathogenic | Cardiovascular phenotype | 2023-06-02 | criteria provided, single submitter | clinical testing | The c.2398+5G>T intronic variant results from a G to T substitution 5 nucleotides after coding exon 9 in the KCNH2 gene. This variant has been detected in several individuals from long QT syndrome (LQTS) cohorts or who were referred for LQTS genetic testing; however, some reports may overlap and details were limited (Kapa S et al. Circulation, 2009 Nov;120:1752-60; Kapplinger JD et al. Heart Rhythm, 2009 Sep;6:1297-303; Anderson JH et al. Heart Rhythm, 2014 Jan;11:53-7). A minigene study has indicated that this variant may result in aberrant splicing (O'Neill MJ et al. Circ Genom Precis Med, 2022 Dec;15:e003782). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration may result in the creation or strengthening of a novel splice donor site. Based on the majority of available evidence to date, this variant is likely to be pathogenic. |