rs199472777
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 0P and 0B.
The NM_000218.3(KCNQ1):c.1193A>G(p.Lys398Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000178 in 1,461,650 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Consequence
NM_000218.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 0 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
KCNQ1 | ENST00000155840.12 | c.1193A>G | p.Lys398Arg | missense_variant | Exon 9 of 16 | 1 | NM_000218.3 | ENSP00000155840.2 | ||
KCNQ1 | ENST00000335475.6 | c.812A>G | p.Lys271Arg | missense_variant | Exon 9 of 16 | 1 | ENSP00000334497.5 | |||
KCNQ1 | ENST00000496887.7 | c.836A>G | p.Lys279Arg | missense_variant | Exon 9 of 16 | 5 | ENSP00000434560.2 | |||
KCNQ1 | ENST00000646564.2 | c.653A>G | p.Lys218Arg | missense_variant | Exon 4 of 11 | ENSP00000495806.2 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD4 exome AF: 0.0000178 AC: 26AN: 1461650Hom.: 0 Cov.: 32 AF XY: 0.0000248 AC XY: 18AN XY: 727128
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
Long QT syndrome Uncertain:2
This sequence change replaces lysine, which is basic and polar, with arginine, which is basic and polar, at codon 398 of the KCNQ1 protein (p.Lys398Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of KCNQ1-related conditions (PMID: 19716085, 34930020, 36806574). ClinVar contains an entry for this variant (Variation ID: 67021). 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) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on KCNQ1 protein function. Experimental studies have shown that this missense change affects KCNQ1 function (PMID: 34930020). 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. -
This missense variant replaces lysine with arginine at codon 398 of the KCNQ1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual suspected to be affected with long QT syndrome (PMID: 19716085), in an individual affected with short QT syndrome (PMID: 36806574), in an individual affected with idiopathic ventricular fibrillation (PMID: 31114860), and in an individual affected with left bundle branch block as well as an unaffected carrier (PMID: 34930020). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
Beckwith-Wiedemann syndrome;C1837014:Atrial fibrillation, familial, 3;C1865019:Short QT syndrome type 2;C4551509:Jervell and Lange-Nielsen syndrome 1;C4551647:Long QT syndrome 1 Uncertain:1
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Cardiovascular phenotype Uncertain:1
The c.1193A>G (p.K398R) alteration is located in exon 9 (coding exon 9) of the KCNQ1 gene. This alteration results from a A to G substitution at nucleotide position 1193, causing the lysine (K) at amino acid position 398 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -
Cardiac arrhythmia Uncertain:1
This missense variant replaces lysine with arginine at codon 398 of the KCNQ1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual suspected to be affected with long QT syndrome (PMID: 19716085), in an individual affected with short QT syndrome (PMID: 36806574), in an individual affected with idiopathic ventricular fibrillation (PMID: 31114860), and in an individual affected with left bundle branch block as well as an unaffected carrier (PMID: 34930020). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
Congenital long QT syndrome Other:1
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. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at