rs145229963
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM5BP4
The NM_000218.3(KCNQ1):c.1355G>A(p.Arg452Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00017 in 1,613,016 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign 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. R452L) has been classified 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 1 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
KCNQ1 | NM_000218.3 | c.1355G>A | p.Arg452Gln | missense_variant | 10/16 | ENST00000155840.12 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
KCNQ1 | ENST00000155840.12 | c.1355G>A | p.Arg452Gln | missense_variant | 10/16 | 1 | NM_000218.3 | P1 | |
KCNQ1 | ENST00000335475.6 | c.974G>A | p.Arg325Gln | missense_variant | 10/16 | 1 | |||
KCNQ1 | ENST00000496887.7 | c.998G>A | p.Arg333Gln | missense_variant | 10/16 | 5 | |||
KCNQ1 | ENST00000646564.2 | c.815G>A | p.Arg272Gln | missense_variant | 5/11 |
Frequencies
GnomAD3 genomes ? AF: 0.000125 AC: 19AN: 152138Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000921 AC: 23AN: 249712Hom.: 0 AF XY: 0.0000665 AC XY: 9AN XY: 135286
GnomAD4 exome AF: 0.000175 AC: 256AN: 1460878Hom.: 0 Cov.: 32 AF XY: 0.000157 AC XY: 114AN XY: 726714
GnomAD4 genome ? AF: 0.000125 AC: 19AN: 152138Hom.: 0 Cov.: 33 AF XY: 0.0000538 AC XY: 4AN XY: 74310
ClinVar
Submissions by phenotype
Long QT syndrome Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 02, 2024 | This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 452 of the KCNQ1 protein (p.Arg452Gln). This variant is present in population databases (rs145229963, gnomAD 0.02%). This missense change has been observed in individual(s) with KCNQ1-related conditions (PMID: 26318259). ClinVar contains an entry for this variant (Variation ID: 67030). 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 not expected to disrupt KCNQ1 protein function with a negative predictive value of 80%. 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Jan 11, 2024 | This missense variant replaces arginine with glutamine at codon 452 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 not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 31/281090 chromosomes 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jun 14, 2016 | - - |
not provided Uncertain:1Other:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Aug 17, 2023 | Reported in two individuals from one family with LQTS (Ruwald et al., 2020) and present in control cohorts (Kapa et al., 2009); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 19841300, 22581653, 25854863, 22949429, 29197658, 31696929, 26318259) - |
not provided, no classification provided | literature only | Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust | - | This variant has been reported in the following publications (PMID:19841300). - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Aug 17, 2020 | Variant summary: KCNQ1 c.1355G>A (p.Arg452Gln) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00011 in 283970 control chromosomes (gnomAD and publication data). The observed variant frequency is approximately 1.1 fold of the estimated maximal expected allele frequency for a pathogenic variant in KCNQ1 causing Arrhythmia phenotype (0.0001), strongly suggesting that the variant is benign. c.1355G>A has been reported in the literature in individuals affected with Arrhythmia and long QT syndrome type 1 as well as in healthy controls (Kapa_2009, Ruwald_2016, Clemens_2018, Li_2019). These reports do not provide unequivocal conclusions about association of the variant with Arrhythmia. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly benign. - |
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
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Feb 03, 2022 | - - |
Familial atrial fibrillation Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jun 14, 2016 | - - |
Atrial fibrillation, familial, 3;C1865019:Short QT syndrome type 2;C4551647:Long QT syndrome 1 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | New York Genome Center | May 15, 2023 | The c.1355G>A p.(Arg452Gln) missense variant identified in the KCNQ1 gene has been reported in the literature in individuals affected with Arrhythmia and long QT syndrome type 1 as well as in healthy controls (PMID: 19841300, 26318259, 29197658). The c.1355G>A variant has been deposited in ClinVar with conflicting interpretations of pathogenicity by multiple submitters, including ten Uncertain significance and one Likely benign entry [ClinVar ID: 67030]. The variant has an allele frequency of 0.0000951 (56 out of 588,570 heterozygous alleles, no homozygotes) in population databases (gnomAD v2.1.1 and v3.1.2,TOPMed Freeze 8). The c.1355G>A The c.1355G>A variant is located in exon 10 of this 16-exon gene and is predicted to replace a moderately conserved arginine residue with glutamine at position 452 of the encoded protein. In silico predictions are in favor of the variants damaging effect [REVEL = 0.644]; however, functional studies to support or refute these predictions have not been reported. Due to the lack of compelling evidence for its pathogenicity, the c.1355G>Ap.(Arg452Gln) missense variant identified in the KCNQ1 gene is reported as a Variant of Uncertain Significance. - |
Congenital long QT syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jun 14, 2016 | - - |
Short QT syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jun 14, 2016 | - - |
Jervell and Lange-Nielsen syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jun 14, 2016 | - - |
Cardiac arrhythmia Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Jan 27, 2023 | This missense variant replaces arginine with glutamine at codon 452 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 a proband affected with long QT syndrome (PMID: 26318259). This variant has been identified in 31/281090 chromosomes 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. - |
Cardiovascular phenotype Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 13, 2023 | 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at