ClinVar Miner

Submissions for variant NM_181798.1(KCNQ1):c.49A>G (p.Thr17Ala) (rs199473451)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 4
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000463475 SCV000543293 likely pathogenic Long QT syndrome 2020-05-20 criteria provided, single submitter clinical testing This sequence change replaces threonine with alanine at codon 144 of the KCNQ1 protein (p.Thr144Ala). The threonine residue is highly conserved and there is a small physicochemical difference between threonine and alanine. This variant is not present in population databases (rs199473451, ExAC no frequency). This variant has been reported in several individuals affected with long QT syndrome who did not carry other variants in the KCNQ1 gene (PMID: 14678125, 17470695). This variant was also shown to be on the same allele as KCNQ1 p.Arg594Pro in two families, and this combination of variants segregated with long QT syndrome in both families (PMID: 17224687, Invitae database). ClinVar contains an entry for this variant (Variation ID: 67073). Experimental studies have shown that this missense change has some disruptive effect on channel function (PMID: 23271449). In summary, this variant is absent from population databases and has been shown to independently segregate with long QT syndrome. In the absence of functional evidence or additional segregation data, at this time this variant has been classified as Likely Pathogenic.
GeneDx RCV000489920 SCV000576622 uncertain significance not provided 2018-09-04 criteria provided, single submitter clinical testing The T144A variant of uncertain significance in the KCNQ1 gene has previously been reported in multiple unrelated individuals with LQTS (Zareba et al., 2003; Miller et al., 2007; Moss et al., 2007; Kapplinger et al., 2009). Miller et al. (2007) identified T144A in one individual with LQTS who also harbored another variant (R594P) on the same KCNQ1 allele (in cis). The T144A variant has also been identified in conjunction with the KCNQ1 R594P variant in several unrelated individuals referred for LQTS genetic testing at GeneDx. So far, testing in other families was consistent with the variants occurring in cis; segregation data is otherwise unavailable.The T144A variant is not observed in large population cohorts (Lek et al., 2016). The T144A variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position within the S1-S2 linker region of KCNQ1 at a position that is conserved across species (Wang et al., 2011). In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Functional studies by Full et al. (2013) demonstrated the T144A variant resulted in decreased potassium currents with slowed activation, accelerated deactivation kinetics, and a depolarizing shift in the voltage dependence of activation when expressed in homologous potassium channel genes (KCNQ2/3). However, direct analysis of the effect of the T144A variant on the KCNQ1 protein was not performed. Furthermore, despite the fact that multiple publications describe an association between the T144A variant in the KCNQ1 gene and LQTS, family history information and segregation data is limited.
Ambry Genetics RCV000618499 SCV000738071 uncertain significance Cardiovascular phenotype 2017-06-27 criteria provided, single submitter clinical testing The p.T144A variant (also known as c.430A>G), located in coding exon 2 of the KCNQ1 gene, results from an A to G substitution at nucleotide position 430. The threonine at codon 144 is replaced by alanine, an amino acid with similar properties, and is located in the S1-S2 domain. This variant has been associated with long QT syndrome (LQTS) in a few individuals, but clinical details were limited and at least one of the individuals harbored another KCNQ1 alteration (p.R594P) in cis (Zareba W et al. J. Cardiovasc. Electrophysiol. 2003;14:1149-53; Miller TE et al. Genet. Med. 2007;9:23-33; Kapplinger JD et al. Heart Rhythm. 2009;6:1297-303). The equivalent alterations in KCNQ1 paralogs KCNQ2 (p.T114A) and KCNQ3 (p.T144A) lead to deficient protein function in vitro; however, no similar studies have been performed for this alteration (Füll Y et al. Pflugers Arch. 2013;465:797-804). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust RCV000057675 SCV000089194 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:14678125;PMID:17224687;PMID:19716085;PMID:17470695). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.