Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Color Diagnostics, |
RCV001842062 | SCV001733877 | uncertain significance | Cardiac arrhythmia | 2020-11-17 | criteria provided, single submitter | clinical testing | This missense variant replaces arginine with lysine at codon 380 of the KCNQ1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. |
| Victorian Clinical Genetics Services, |
RCV004789645 | SCV005399363 | likely pathogenic | Long QT syndrome 1 | 2022-09-02 | criteria provided, single submitter | clinical testing | Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Likely pathogenic. Following criteria are met: 0103 - Dominant negative, loss of function and gain of function are known mechanisms of disease in this gene. Gain of function variants result exclusively in short QT syndrome (MIM#609621), while dominant negative and loss of function variants can cause long QT syndrome (LQTS, MIM#192500), atrial fibrillation (MIM#607554) and Jervell and Lange-Nielsen syndrome (JLNS, MIM#220400) (OMIM, PMIDs: 19632626, 28438721). (I) 0108 - This gene is known to be associated with both recessive and dominant disease. JLNS is characterised by congenital, bilateral deafness and variable degrees of QT prolongation, and is the only condition caused by biallelic pathogenic KCNQ1 variants (PMID: 28438721). (I) 0112 - The condition associated with this gene has incomplete penetrance (OMIM, PMID: 20301308). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to lysine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0702 - Other missense variants comparable to the one identified in this case have strong previous evidence for pathogenicity. p.(Arg380Ser) and p.(Arg380Gly) have been reported in at least four unrelated individuals with long QT syndrome (PMIDs: 15840476, 19841300, 32893267, 26344792, 29654130, 19841298), and the former has been reported as pathogenic in a clinical laboratory (ClinVar). In addition, p.(Arg380Trp) has been reported as a VUS (ClinVar), and p.(Arg380Gln) has been reported in a HCM cohort (PMID: 25351510). (SP) 0809 - Previous evidence of pathogenicity for this variant is inconclusive. It has been reported as a VUS and heterozygous in an individual, however no further clinical information is available (ClinVar, personal communication). (I) 0903 - This variant has limited evidence for segregation with disease. It is heterozygous in the father and two siblings of this individual who have symptoms suggestive of long QT syndrome (VCGS). (SP) 1007 - No published functional evidence has been identified for this variant. (I) 1206 - This variant has been shown to be paternally inherited (VCGS #39501). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign |