Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, |
RCV001256905 | SCV001433410 | likely pathogenic | Long QT syndrome 1 | 2019-01-08 | criteria provided, single submitter | clinical testing | |
| Victorian Clinical Genetics Services, |
RCV002471062 | SCV002768465 | uncertain significance | Long QT syndrome 2 | 2020-10-19 | criteria provided, single submitter | clinical testing | Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as VUS - 3A. Following criteria are met: 0103 - Both loss- and gain-of-function are known mechanisms of disease for this gene. Variants predicted to undergo nonsense-mediated decay have a loss of function mechanism, while missense have been reported to have a dominant negative, and both loss and gain of function effects on protein function (OMIM, PMID: 10753933, PMID: 21777565). (N) 0104 - Dominant Negative is a mechanism of disease for this gene. (N) 0107 - This gene is known to be associated with autosomal dominant disease. Loss of function and dominant negative mutations cause Long QT syndrome, while gain of function mutations cause Short QT syndrome (OMIM, PMID: 10753933, PMID: 21777565). (N) 0200 - Variant is predicted to result in a missense amino acid change from leucine to proline (exon 7). (N) 0251 - Variant is heterozygous. (N) 0301 - Variant is absent from gnomAD. (P) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (P) 0601 - Variant affects at least one well-established (essential) functional domain or motif. This variant is present in the S4 region of the ion transporter domain. Functional studies on alternative missense changes of this residue (p.Leu532Trp, p.Leu532Ser) impaired deactivation rate and decreased the equilibrium constant (PMID: 23980196, PMID: 16166152). (P) 0705 - No comparable variants have previous evidence for pathogenicity. (N) 0807 - Variant has not previously been reported in a clinical context. (N) 0905 - No segregation evidence has been identified for this variant. (N) 1002 - Moderate functional evidence supporting abnormal protein function. Transfected HEK293 cells demonstrate a positive shift in inactivation and activation voltage and faster current repolarization (PMID: 21777565). (P) 1208 - Inheritance information for this variant is not currently available. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign |