ClinVar Miner

Submissions for variant NM_000218.3(KCNQ1):c.506C>T (p.Thr169Met)

gnomAD frequency: 0.00001  dbSNP: rs199472693
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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp 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, LLC DBA Color Health 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, Johns Hopkins University RCV001250549 SCV001425371 uncertain significance Long QT syndrome 1 2020-05-14 criteria provided, single submitter clinical testing
Fulgent Genetics, 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, Molecular Genetics and Genomics, 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, National Institutes of Health 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.

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