rs74315446
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1PP3_Moderate
The NM_000219.6(KCNE1):c.221C>T(p.Ser74Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000756 in 1,455,162 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S74A) has been classified as Uncertain significance.
Frequency
Consequence
NM_000219.6 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Uncertain_significance. Variant got 4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
KCNE1 | NM_000219.6 | c.221C>T | p.Ser74Leu | missense_variant | 4/4 | ENST00000399286.3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
KCNE1 | ENST00000399286.3 | c.221C>T | p.Ser74Leu | missense_variant | 4/4 | 1 | NM_000219.6 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00 AC: 2AN: 140560Hom.: 0 Cov.: 17 FAILED QC
GnomAD3 exomes AF: 0.0000159 AC: 4AN: 251392Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135892
GnomAD4 exome AF: 0.00000756 AC: 11AN: 1455162Hom.: 0 Cov.: 29 AF XY: 0.00000828 AC XY: 6AN XY: 724338
GnomAD4 genome ? Data not reliable, filtered out with message: AS_VQSR AF: 0.0000142 AC: 2AN: 140672Hom.: 0 Cov.: 17 AF XY: 0.0000294 AC XY: 2AN XY: 68142
ClinVar
Submissions by phenotype
Long QT syndrome 5 Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Nov 01, 1997 | - - |
Long QT syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Oct 28, 2023 | 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. - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Apr 29, 2016 | 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. - |
Long QT syndrome 5;C2676723:Jervell and Lange-Nielsen syndrome 2 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Nov 01, 2021 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jul 25, 2023 | 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) - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 15, 2018 | The c.221C>T (p.S74L) alteration is located in exon 3 (coding exon 1) of the KCNE1 gene. This alteration results from a C to T substitution at nucleotide position 221, causing the serine (S) at amino acid position 74 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Congenital long QT syndrome Other:1
not provided, no classification provided | literature only | Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust | - | 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at