ClinVar Miner

Submissions for variant NM_000218.2(KCNQ1):c.1016T>C (p.Phe339Ser) (rs199472759)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust RCV000057525 SCV000089044 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:17224687;PMID:17905336;PMID:19808498). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.
Center for Human Genetics and Laboratory Diagnostics, Dr. Klein, Dr. Rost and Colleagues RCV000515709 SCV000611760 pathogenic Long QT syndrome 1 2017-07-28 criteria provided, single submitter clinical testing
GeneDx RCV000182311 SCV000234614 pathogenic not provided 2018-09-21 criteria provided, single submitter clinical testing The F339S pathogenic variant in the KCNQ1 gene has been reported in several unrelated individuals with LQTS (Chung et al; 2007; Miller et al., 2007; Yang et al., 2009; Hoosien et al; 2013; Riuro et al., 2014; Itoh et al., 2015). In one of these cases, it was reported as a de novo variant in a one month old infant diagnosed with LQTS, whose parents did not harbor this variant although identity studies were not performed (Miller et al., 2007; Hoosien et al. 2013). The F339S variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Additionally, F339S 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 within the S6 transmembrane segment of the KCNQ1 channel, at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Furthermore, voltage clamp studies in both Xenopus oocytes and Chinese hamster ovary cells have shown that F339S causes a reduced delayed rectifier current (Yang et al., 2009; Hoosien et al., 2013). Moreover, pathogenic/likely pathogenic missense variants in nearby residues (A341V, A341E, A344V, A344G) have been reported in the Human Gene Mutation Database in association with LQTS (Stenson et al., 2014), supporting the functional importance of this region of the protein.In summary, F339S in the KCNQ1 gene is interpreted as a pathogenic variant.
SIB Swiss Institute of Bioinformatics RCV000515709 SCV000883302 likely pathogenic Long QT syndrome 1 2018-10-15 criteria provided, single submitter curation This variant is interpreted as Likely Pathogenic, for Long QT syndrome 1, autosomal dominant. The following ACMG Tag(s) were applied: PM2 => Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. PP3 => Multiple lines of computational evidence support a deleterious effect on the gene or gene product. PS3 => Well-established functional studies show a deleterious effect (https://www.ncbi.nlm.nih.gov/pubmed/19808498).

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