Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV001842618 | SCV001338647 | likely pathogenic | Cardiac arrhythmia | 2020-04-20 | criteria provided, single submitter | clinical testing | Variant summary: KCNH2 c.3092delG (p.Gly1031ValfsX26) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant was absent in 147244 control chromosomes. To our knowledge, no occurrence of c.3092delG in individuals affected with Arrhythmia and no experimental evidence demonstrating its impact on protein function have been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely pathogenic. |
| Invitae | RCV001383848 | SCV001583157 | pathogenic | Long QT syndrome | 2020-01-13 | criteria provided, single submitter | clinical testing | Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in KCNH2 are known to be pathogenic (PMID: 10973849, 19862833). This variant has not been reported in the literature in individuals with KCNH2-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Gly1031Valfs*26) in the KCNH2 gene. It is expected to result in an absent or disrupted protein product. |
| Ambry Genetics | RCV003163386 | SCV003864690 | pathogenic | Cardiovascular phenotype | 2023-01-27 | criteria provided, single submitter | clinical testing | The c.3092delG pathogenic mutation, located in coding exon 13 of the KCNH2 gene, results from a deletion of one nucleotide at nucleotide position 3092, causing a translational frameshift with a predicted alternate stop codon (p.G1031Vfs*26). This variant has been detected in an individual from a long QT syndrome cohort (Walsh R et al. Genet Med, 2021 Jan;23:47-58). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. |