Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV001841180 | SCV001360749 | likely pathogenic | Cardiac arrhythmia | 2019-09-23 | criteria provided, single submitter | clinical testing | Variant summary: KCNH2 c.3100_3107delinsGGC (p.Pro1034GlyfsX83) 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 145010 control chromosomes (gnomAD). c.3100_3107delinsGGC has been reported in the literature in one patient being tested for LQTS (Kapplinger_2009). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has 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. |
| Ambry Genetics | RCV003293979 | SCV003997360 | pathogenic | Cardiovascular phenotype | 2023-06-05 | criteria provided, single submitter | clinical testing | The c.3100_3107delCCCCGGGGinsGGC pathogenic mutation, located in coding exon 13 of the KCNH2 gene, results from the deletion of 8 nucleotides and insertion of 3 nucleotides causing a translational frameshift with a predicted alternate stop codon (p.P1034Gfs*83). This variant has been detected in a long QT syndrome genetic testing cohort (Kapplinger JD et al. Heart Rhythm. 2009 Sep;6(9):1297-303). This alteration occurs at the 3' terminus of theKCNH2 gene, is not expected to trigger nonsense-mediated mRNA decay, and impacts the last 126 amino acids (10.9%) of the protein. However, premature stop codons are typically deleterious in nature, a significant portion of the protein is affected, and the impacted region is critical for protein function (Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. |