Total submissions: 8
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Labcorp Genetics |
RCV000457132 | SCV000543321 | uncertain significance | Long QT syndrome | 2022-03-09 | criteria provided, single submitter | clinical testing | This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 169 of the KCNQ1 protein (p.Thr169Met). This variant is present in population databases (rs199472693, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with KCNQ1-related conditions. ClinVar contains an entry for this variant (Variation ID: 405270). 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 tolerated. Experimental studies have shown that this missense change affects KCNQ1 function (PMID: 29532034, 30571187). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. |
Color Diagnostics, |
RCV001841346 | SCV001356683 | uncertain significance | Cardiac arrhythmia | 2021-01-04 | criteria provided, single submitter | clinical testing | This missense variant replaces threonine with methionine at codon 169 of the KCNQ1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 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 been identified in 12/249616 chromosomes 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. |
Johns Hopkins Genomics, |
RCV001250549 | SCV001425371 | uncertain significance | Long QT syndrome 1 | 2020-05-14 | criteria provided, single submitter | clinical testing | |
Fulgent Genetics, |
RCV002502613 | SCV002781054 | uncertain significance | Atrial fibrillation, familial, 3; Beckwith-Wiedemann syndrome; Long QT syndrome 1; Jervell and Lange-Nielsen syndrome 1; Short QT syndrome type 2 | 2021-10-13 | criteria provided, single submitter | clinical testing | |
New York Genome Center | RCV003227751 | SCV003925296 | uncertain significance | Atrial fibrillation, familial, 3; Long QT syndrome 1; Jervell and Lange-Nielsen syndrome 1; Short QT syndrome type 2 | 2022-08-28 | criteria provided, single submitter | clinical testing | |
Ambry Genetics | RCV003372716 | SCV004082274 | uncertain significance | Cardiovascular phenotype | 2023-08-30 | criteria provided, single submitter | clinical testing | The p.T169M variant (also known as c.506C>T), located in coding exon 3 of the KCNQ1 gene, results from a C to T substitution at nucleotide position 506. The threonine at codon 169 is replaced by methionine, an amino acid with similar properties. Functional analysis suggests this alteration causes a moderate decrease in potassium current density; however, the physiological relevance of result is unclear (Huang H et al. Sci Adv, 2018 03;4:eaar2631; Vanoye CG et al. Circ Genom Precis Med, 2018 Nov;11:e002345). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |
ARUP Laboratories, |
RCV003736774 | SCV004563632 | uncertain significance | not provided | 2023-04-20 | criteria provided, single submitter | clinical testing | The KCNQ1 c.506C>T; p.Thr169Met variant (rs199472693), to our knowledge is not reported in the medical literature but is reported in ClinVar (Variation ID: 405270). This variant is found in the general population with an overall allele frequency of 0.005% (12/249616 alleles) in the Genome Aggregation Database. In vitro functional analyses demonstrate that this variant may cause a reduction on ion channel conductance (Huang 2018, Vanoye 2018). Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.507). Given the lack of clinical information, the significance of the p.Thr169Met variant is uncertain at this time. References: Huang H et al. Mechanisms of KCNQ1 channel dysfunction in long QT syndrome involving voltage sensor domain mutations. Sci Adv. 2018 Mar 7;4(3):eaar2631. PMID: 29532034. Vanoye CG et al. High-Throughput Functional Evaluation of KCNQ1 Decrypts Variants of Unknown Significance. Circ Genom Precis Med. 2018 Nov;11(11):e002345. PMID: 30571187. |
All of Us Research Program, |
RCV000457132 | SCV005426293 | uncertain significance | Long QT syndrome | 2024-09-23 | criteria provided, single submitter | clinical testing | This missense variant replaces threonine with methionine at codon 169 of the KCNQ1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 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 been identified in 12/249616 chromosomes 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. |