ClinVar Miner

Submissions for variant NM_000219.6(KCNE1):c.137A>G (p.Tyr46Cys)

gnomAD frequency: 0.00003  dbSNP: rs1402178514
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000612549 SCV000731302 likely pathogenic Rare genetic deafness 2017-03-07 criteria provided, single submitter clinical testing The p.Tyr46Cys variant in KCNE1 has been identified by our laboratory in the hom ozygous state in 1 individual with clinical features of Jervell and Lange-Nielse n syndrome (JLNS) and segregated in an affected sibling. This variant has been identified in 1/3494 Finnish chromosomes by the Genome Aggregation Database (gno mAD, http://gnomad.broadinstitute.org). Computational prediction tools and conse rvation analyses suggest that this variant may impact the protein, though this i nformation is not predictive enough to determine pathogenicity. In summary, alth ough additional studies are required to fully establish its clinical significanc e, this variant is likely pathogenic for autosomal recessive JLNS.
Ambry Genetics RCV002385950 SCV002696444 uncertain significance Cardiovascular phenotype 2023-08-16 criteria provided, single submitter clinical testing The p.Y46C variant (also known as c.137A>G), located in coding exon 1 of the KCNE1 gene, results from an A to G substitution at nucleotide position 137. The tyrosine at codon 46 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration has been reported in a long QT syndrome cohort; however, clinical details were limited (Roberts JD et al. Circulation, 2020 Feb;141:429-439). Limited functional studies have suggested this alteration may impact current amplitudes and pore conductance (Wang Y et al. J. Gen. Physiol., 2012 Dec;140:653-69). 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.
Stanford Center for Inherited Cardiovascular Disease, Stanford University RCV000786138 SCV000924804 likely pathogenic not provided 2017-03-09 no assertion criteria provided provider interpretation
Roden Lab, Vanderbilt University Medical Center RCV004777761 SCV005393160 not provided Long QT syndrome 5 no assertion provided in vitro

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