Submissions for variant NM_000219.6(KCNE1):c.163G>A (p.Gly55Ser)

gnomAD frequency: 0.00003  dbSNP: rs199473644

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000150858	SCV000198416	uncertain significance	not specified	2014-02-10	criteria provided, single submitter	clinical testing	Variant classified as Uncertain Significance - Favor Benign. The Gly55Ser varian t in KCNE1 has not been previously reported in any individuals with hearing loss and was absent from large population studies. However, this variant has been re ported in one individual with long QT syndrome (Kapplinger 2009). The glycine (G ly) residue at position 55 is not conserved across several species including two mammals (hamster and mole) having serine (Ser) at this position, suggesting tha t the variant may be tolerated. However, this information is not sufficient to r ule out pathogenicity. In summary, the clinical significance of this variant can not be determined with certainty; however based upon the conservation data, we w ould lean towards a more likely benign role.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000463748	SCV000549147	uncertain significance	Long QT syndrome	2024-10-31	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 55 of the KCNE1 protein (p.Gly55Ser). This variant is present in population databases (rs199473644, gnomAD 0.05%). This missense change has been observed in individual(s) with clinical features of LQTS (PMID: 19716085, 31941373). ClinVar contains an entry for this variant (Variation ID: 132657). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt KCNE1 protein function with a negative predictive value of 95%. Experimental studies have shown that this missense change affects KCNE1 function (PMID: 17545244). 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.
GeneDx	RCV000786139	SCV001769652	uncertain significance	not provided	2020-12-01	criteria provided, single submitter	clinical testing	Reported in one individual referred for LQTS genetic testing (Kapplinger et al., 2009); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Reported as a variant of uncertain significance by other clinical laboratories in ClinVar (SCV000549147.3, SCV000198416.4; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 24710009, 19716085, 31941373, 28988457)
Ambry Genetics	RCV002399485	SCV002704558	likely benign	Cardiovascular phenotype	2022-09-14	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Fulgent Genetics, Fulgent Genetics	RCV002477299	SCV002785867	uncertain significance	Jervell and Lange-Nielsen syndrome 2; Long QT syndrome 5	2021-09-08	criteria provided, single submitter	clinical testing
Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust	RCV000119069	SCV000153788	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:19716085). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000786139	SCV000924805	uncertain significance	not provided	2018-01-12	no assertion criteria provided	provider interpretation	Variant KCNE1 p.Gly55Ser (c.163G>A) exon 4 (NM_000219.5, hg19 chr21-35821770-C-T) SCICD classification variant of uncertain significance, probably benign We do not feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). The rationale for this assessment is: too high MAF. (rs199473644, ExAC 0.07%)" 0.05198% MAF in South Asians
Roden Lab, Vanderbilt University Medical Center	RCV004777582	SCV005393246	not provided	Long QT syndrome 5		no assertion provided	in vitro