Submissions for variant NM_000219.6(KCNE1):c.221C>T (p.Ser74Leu)

gnomAD frequency: 0.00001  dbSNP: rs74315446

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000471661	SCV000549145	pathogenic	Long QT syndrome	2023-10-28	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 74 of the KCNE1 protein (p.Ser74Leu). This variant is present in population databases (rs74315446, gnomAD 0.005%). This missense change has been observed in individuals with long QT syndrome (PMID: 9354802, 31941373; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 13478). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt KCNE1 protein function with a positive predictive value of 80%. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on KCNE1 function (PMID: 9354802, 9834138, 19008479, 19907016, 32058015). For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000603252	SCV000711387	uncertain significance	not specified	2016-04-29	criteria provided, single submitter	clinical testing	Variant classified as Uncertain Significance - Favor Pathogenic. The p.Ser74Leu variant in KCNE1 has been previously reported in one individual with long-QT syn drome and reportedly segregated in two family members with elevated QTc interval s who did not display overt symptoms (Splawski 1997, Westenskow 2004). This vari ant has been identified in 2/66630 European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs74315446). Computatio nal prediction tools and conservation analysis suggest that this variant may imp act the protein. In addition, in vitro functional studies provide some evidence that the p.Ser74Leu variant may have a mild effect on the normal function of the protein (Harmer 2010, McCrossan 2009, Sesti 1998). However, these types of assa ys may not accurately represent biological function. In summary, while there is some suspicion for a pathogenic role based on the reported family and in vitro s tudies, the clinical significance of this variant is uncertain.
Fulgent Genetics, Fulgent Genetics	RCV002482866	SCV002782964	uncertain significance	Jervell and Lange-Nielsen syndrome 2; Long QT syndrome 5	2021-11-01	criteria provided, single submitter	clinical testing
GeneDx	RCV003318541	SCV004022801	uncertain significance	not provided	2023-07-25	criteria provided, single submitter	clinical testing	Functional studies have not been consistent in showing p.(S74L) has a damaging effect on channel function (Splawski et al., 1997; Garmany et al., 2020; Strutz-Seebohm et al., 2006; Chen et al., 2020); This variant is associated with the following publications: (PMID: 19907016, 9834138, 10973849, 16914890, 36921038, 30461122, 30930557, 37162834, 29661707, 32058015, 31834838, 19008479, 9354802, 31941373, 31521807, 24710009)
OMIM	RCV000014421	SCV000034670	pathogenic	Long QT syndrome 5	1997-11-01	no assertion criteria provided	literature only
Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust	RCV000119079	SCV000153798	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:9354802;PMID:15051636;PMID:19907016). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.