rs36210419
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1PM2
The NM_000218.3(KCNQ1):c.652A>G(p.Lys218Glu) variant causes a missense change. The variant allele was found at a frequency of 0.000000685 in 1,460,726 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K218R) has been classified as Uncertain significance.
Frequency
Consequence
NM_000218.3 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 |
---|---|---|---|---|---|---|---|
KCNQ1 | NM_000218.3 | c.652A>G | p.Lys218Glu | missense_variant | 4/16 | ENST00000155840.12 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
KCNQ1 | ENST00000155840.12 | c.652A>G | p.Lys218Glu | missense_variant | 4/16 | 1 | NM_000218.3 | P1 | |
KCNQ1 | ENST00000335475.6 | c.271A>G | p.Lys91Glu | missense_variant | 4/16 | 1 | |||
KCNQ1 | ENST00000496887.7 | c.391A>G | p.Lys131Glu | missense_variant | 5/16 | 5 | |||
KCNQ1 | ENST00000646564.2 | c.478-12063A>G | intron_variant |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD4 exome AF: 6.85e-7 AC: 1AN: 1460726Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1AN XY: 726722
GnomAD4 genome ? Cov.: 33
ClinVar
Submissions by phenotype
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Nov 06, 2017 | The K218E variant in the KCNQ1 gene has been reported one individual with torsades de pointes, however no clinical or segregation information was provided (Mank-Seymore et al., 2006). The K218E variant is not observed in large population cohorts (Lek et al., 2016). The K218E variant 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 at a position conserved in mammals. A majority of in silico analysis predicts this variant is probably damaging to the protein structure/function. Thus, this variant lacks observation in a significant number of affected individuals, segregation data, and functional evidence, which would further clarify its pathogenicity. - |
Long QT syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jul 14, 2021 | 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. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on KCNQ1 protein function (PMID: 29532034, 30571187). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 67095). This variant has been observed in individual(s) with torsades de pointes (PMID: 17161064). This variant is not present in population databases (ExAC no frequency). This sequence change replaces lysine with glutamic acid at codon 218 of the KCNQ1 protein (p.Lys218Glu). The lysine residue is moderately conserved and there is a small physicochemical difference between lysine and glutamic acid. - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 15, 2018 | The c.652A>G (p.K218E) alteration is located in exon 4 (coding exon 4) of the KCNQ1 gene. This alteration results from a A to G substitution at nucleotide position 652, causing the lysine (K) at amino acid position 218 to be replaced by a glutamic acid (E). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Torsades de pointes 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 torsades de pointes in the following publications (PMID:17161064). 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