Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000182130 | SCV000234433 | pathogenic | not provided | 2023-12-13 | criteria provided, single submitter | clinical testing | Identified in patients with LQTS and JLNS referred for genetic testing at GeneDx and in published literature (PMID: 9020846, 9781056, 15840476, 19490272, 19716085, 22456477, 23158531); Observed in homozygous state in a patient in published literature with JLNS and not observed in homozygous state in controls (PMID: 9781056, 9020846); Published functional studies demonstrate a damaging effect as the W305S variant results in decreased potassium channel current (PMID: 9312006); Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 19716085, 26344792, 9781056, 34505893, 10973849, 17999538, 15840476, 19490272, 23158531, 21451124, 22456477, 26669661, 32383558, 34076677, 9020846, 9312006) |
| Ambry Genetics | RCV000622153 | SCV000738133 | pathogenic | Cardiovascular phenotype | 2022-03-31 | criteria provided, single submitter | clinical testing | The p.W305S variant (also known as c.914G>C), located in coding exon 6 of the KCNQ1 gene, results from a G to C substitution at nucleotide position 914. The tryptophan at codon 305 is replaced by serine, an amino acid with highly dissimilar properties, and is located in the pore region of the protein. This variant has been reported in individuals and families with long QT syndrome (LQTS), as well as in LQTS clinical genetic testing cohorts; however, individual clinical details were limited (Tester DJ et al. Heart Rhythm, 2005;2:507-17; Jons C et al. Sci Transl Med, 2011 Mar;3:76ra28; Itoh H et al. Eur J Hum Genet, 2016 08;24:1160-6). This alteration was also detected in three homozygous cases, including two siblings and an unrelated proband, with autosomal recessive Jervell and Lange-Nielsen syndrome (Neyroud N et al. Eur. J. Hum. Genet. 1998;6:129-33). In vitro functional analyses suggest that this variant significantly reduces potassium current, although in one study the impact was lessened when the alteration was co-expressed with wildtype KCNQ1 (Chouabe C et al. EMBO J. 1997;16:5472-9; Jons C et al. Sci Transl Med. 2011;3:76ra28). Internal structural analysis indicates that this alteration is moderately disruptive in a sensitive region and more disruptive than a nearby known pathogenic variant (Ambry internal data). In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. |
| Labcorp Genetics |
RCV001385529 | SCV001585411 | pathogenic | Long QT syndrome | 2022-04-30 | criteria provided, single submitter | clinical testing | This sequence change replaces tryptophan, which is neutral and slightly polar, with serine, which is neutral and polar, at codon 305 of the KCNQ1 protein (p.Trp305Ser). This variant is present in population databases (rs120074186, gnomAD 0.0009%). This missense change has been observed in individuals with clinical features of long QT syndrome and Jervell and Lange-Nielsen syndrome (PMID: 9781056, 15840476, 19490272, 19716085, 21451124, 22456477, 23139254). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 3127). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects KCNQ1 function (PMID: 9312006, 10090886, 21451124, 26344792). This variant disrupts the p.Trp305 amino acid residue in KCNQ1. Other variant(s) that disrupt this residue have been observed in individuals with KCNQ1-related conditions (PMID: 22949429, 26344792), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. |
| OMIM | RCV000003275 | SCV000023433 | pathogenic | Jervell and Lange-Nielsen syndrome 1 | 1998-03-01 | no assertion criteria provided | literature only | |
| Cardiovascular Biomedical Research Unit, |
RCV000057796 | SCV000089315 | not provided | Congenital long QT syndrome | no assertion provided | literature only | This variant has been reported as associated with Long QT syndrome in the following publications (PMID:9781056;PMID:15840476;PMID:19716085;PMID:9312006;PMID:17999538). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory. |