Submissions for variant NM_000219.6(KCNE1):c.107G>A (p.Arg36His)

gnomAD frequency: 0.00003  dbSNP: rs199473351

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
CSER _CC_NCGL, University of Washington	RCV000590868	SCV000700114	uncertain significance	Long QT syndrome	2016-10-01	criteria provided, single submitter	research	Found in patient having exome sequencing for an unrelated indication. No known history of long QT syndrome. This interpretation considers GERP score and allele frequency data, in addition to published reports of the variant in the literature, available at the time of review.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000605056	SCV000711993	uncertain significance	not specified	2019-01-31	criteria provided, single submitter	clinical testing	Variant classified as Uncertain Significance - Favor Pathogenic. The p.Arg36His variant in KCNE1 has been previously identified in 1 Caucasian individual with long QT syndrome (Napolitano 2005) and 1 individual with hearing loss by our laboratory. It has also been identified in 11/121094 of the total chromosomes across several populations by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs199473351). Computational prediction tools and conservation analysis suggest that the p.Arg36His variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. In summary, the clinical significance of the p.Arg36His variant is uncertain. ACMG/AMP criteria applied: PM2_Supporting, BP4.
Invitae	RCV000590868	SCV001007347	likely benign	Long QT syndrome	2024-01-24	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000866274	SCV001153553	uncertain significance	not provided	2016-10-01	criteria provided, single submitter	clinical testing
GeneDx	RCV000866274	SCV001781935	uncertain significance	not provided	2023-04-28	criteria provided, single submitter	clinical testing	Identified in individuals with suspected or known LQTS (Napolitano et al., 2005; Rajan et al., 2021), a father and son with a transient QT prolongation phenotype (Lane et al., 2018), and in one family with non-syndromic hearing loss with segregation studies showing non-segregation with disease (Chen et al., 2016); Identified in conjunction with additional cardiogenetic variants in individuals referred for arrhythmia genetic testing at GeneDx, but segregation data is limited or absent at this time; Published functional studies in cultured cells showed that, in the heterozygous state, p.(R36H) reduces the slow delayed rectifier potassium current density (Iks), supporting that this variant may have a loss of function effect (Lane et al., 2018); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 30461122, 24710009, 28988457, 29625280, 17341399, 27965898, 34426522, 34667425, 16414944)
Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust	RCV000119062	SCV000153781	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:16414944). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.