ClinVar Miner

Submissions for variant NM_000219.6(KCNE1):c.173C>T (p.Thr58Ile) (rs747321794)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000414735 SCV000490576 likely pathogenic not provided 2016-08-16 criteria provided, single submitter clinical testing The T58I variant that is likely pathogenic was identified in the KCNE1 gene. It has not beenpublished as a pathogenic variant, nor has it been reported as a benign variant to our knowledge.However, this variant has been reported in one other individual referred for LQTS genetic testing atGeneDx. The T58I variant was not observed in approximately 6,500 individuals of European andAfrican American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a commonbenign variant in these populations. The T58I variant is a non-conservative amino acid substitution,which is likely to impact secondary protein structure as these residues differ in polarity, charge, sizeand/or other properties, and this substitution occurs at a position that is conserved across species. Alikely pathogenic variant at the same residue (T58P) has been reported in the Human Gene MutationDatabase in association with LQTS (Stenson et al., 2014), supporting the functional importance ofthis residue. Furthermore, functional studies of the KCNE1 gene by Melman et al. (2002) concludedthat T58, the central amino acid of a triplet responsible for the specificity of KCNE1 control ofactivation of the potassium channel, is essential for the specific control of voltage-dependent channelactivation characteristics. However, in silico analysis is inconsistent in its predictions as to whether ornot the variant is damaging to the protein structure/function. Therefore, this variant is likely pathogenic.
Invitae RCV000539512 SCV000627406 uncertain significance Long QT syndrome 2019-11-15 criteria provided, single submitter clinical testing This sequence change replaces threonine with isoleucine at codon 58 of the KCNE1 protein (p.Thr58Ile). The threonine residue is highly conserved and there is a moderate physicochemical difference between threonine and isoleucine. This variant is present in population databases (rs747321794, ExAC 0.02%). This variant has been observed in individual(s) with long QT syndrome (PMID: 30461122). ClinVar contains an entry for this variant (Variation ID: 372392). 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, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.
Center for Advanced Laboratory Medicine, UC San Diego Health,University of California San Diego RCV000852543 SCV000995242 likely pathogenic Primary dilated cardiomyopathy 2017-08-29 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001002520 SCV001160480 uncertain significance not specified 2019-05-02 criteria provided, single submitter clinical testing The KCNE1 c.173C>T; p.Thr58Ile variant (rs747321794) is reported in the literature in at least one individual affected with long QT syndrome (Faridi 2019). Additionally, another variant at this codon (c.172A>C; p.Thr58Pro) has been reported in individuals with long QT syndrome (Kapplinger 2009). The p.Thr58Ile variant is reported in ClinVar (Variation ID: 372392), and is found in the Latino population with an allele frequency of 0.023% (8/35,440 alleles) in the Genome Aggregation Database. The threonine at codon 58 is highly conserved, and computational analyses (SIFT: tolerated, PolyPhen-2: probably damaging) predict conflicting effects of this variant on protein structure/function. However, functional analyses of the KCNE1 protein show that threonine 58 is critical for specific control of the voltage-dependent potassium channel, and that the p.Thr58Ile variant results in voltage-independent activation in vitro (Melman 2002). Due to limited information, the clinical significance of the p.Thr58Ile variant is uncertain at this time. References: Faridi R et al. Mutational and phenotypic spectra of KCNE1 deficiency in Jervell and Lange-Nielsen Syndrome and Romano-Ward Syndrome. Hum Mutat. 2019 Feb;40(2):162-176. Kapplinger JD et al. Spectrum and prevalence of mutations from the first 2,500 consecutive unrelated patients referred for the FAMILION long QT syndrome genetic test. Heart Rhythm. 2009 Sep;6(9):1297-303. Melman YF et al. A single transmembrane site in the KCNE-encoded proteins controls the specificity of KvLQT1 channel gating. J Biol Chem. 2002 Jul 12;277(28):25187-94.

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