rs199472728
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1PM5
The NM_000218.3(KCNQ1):āc.820A>Gā(p.Ile274Val) variant causes a missense change. The variant allele was found at a frequency of 0.000199 in 1,613,666 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. I274N) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000218.3 missense
Scores
Clinical Significance
Conservation
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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.820A>G | p.Ile274Val | missense_variant | 6/16 | ENST00000155840.12 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
KCNQ1 | ENST00000155840.12 | c.820A>G | p.Ile274Val | missense_variant | 6/16 | 1 | NM_000218.3 | P1 | |
KCNQ1 | ENST00000335475.6 | c.439A>G | p.Ile147Val | missense_variant | 6/16 | 1 | |||
KCNQ1 | ENST00000496887.7 | c.559A>G | p.Ile187Val | missense_variant | 7/16 | 5 | |||
KCNQ1 | ENST00000646564.2 | c.478-10550A>G | intron_variant |
Frequencies
GnomAD3 genomes ? AF: 0.000125 AC: 19AN: 152214Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.000180 AC: 45AN: 250462Hom.: 1 AF XY: 0.000206 AC XY: 28AN XY: 135708
GnomAD4 exome AF: 0.000207 AC: 302AN: 1461452Hom.: 0 Cov.: 32 AF XY: 0.000210 AC XY: 153AN XY: 727044
GnomAD4 genome ? AF: 0.000125 AC: 19AN: 152214Hom.: 0 Cov.: 33 AF XY: 0.000161 AC XY: 12AN XY: 74378
ClinVar
Submissions by phenotype
Long QT syndrome Uncertain:1Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Nov 11, 2023 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Feb 05, 2024 | This missense variant replaces isoleucine with valine at codon 274 of the KCNQ1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been performed for this variant. Whole-cell patch clamp experiments using transfected CHO cells have suggested that this variant may impact function (PMID: 18222468, 24920132). However, clinical relevance of these observations is not clear. This variant has been reported in individuals affected with sudden infant death syndrome (PMID: 17210839, 18222468) and long QT syndrome (PMID: 17470695). This variant has also been identified in 49/281866 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. - |
SUDDEN INFANT DEATH SYNDROME Pathogenic:1
Likely pathogenic, no assertion criteria provided | research | CSER _CC_NCGL, University of Washington | Jun 01, 2014 | - - |
Long QT syndrome 1 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Dec 12, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Apr 07, 2020 | Variant classified as Uncertain Significance - Favor Benign. The p.Ile274Val variant in KCNQ1 has been reported in the heterozygous state in 1 individual with hearing loss where another variant was not identified on the second copy of the KCNQ1 gene, in at least 1 individual with a prolonged QT interval, and 1 individual with sudden infant death syndrome (Moss 2007, Arnestad 2007, Kapplinger 2009, Amin 2012, Goldenberg 2011, LMM data). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID 67109) and has been identified in 0.02% (30/126372) of European chromosomes and 0.06% (16/25754) of Finnish chromosomes, including 1 homozygote, by gnomAD (http://gnomad.broadinstitute.org/). An in vitro patch-clamp study, in which p.Ile274Val was expressed in cultured mammalian cells, suggested that the variant may impact protein function (Rhodes 2008); ; however, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analysis suggest that the p.Ile274Val variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, the clinical significance of the p.Ile274Val variant is uncertain. ACMG/AMP Criteria applied: PP3, PS3_Supporting. - |
Atrial fibrillation, familial, 3 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Dec 12, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. - |
Jervell and Lange-Nielsen syndrome 1 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Dec 12, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jul 07, 2022 | Published functional studies suggest the p.(I274V) variant may alter protein interactions under various experimental conditions; however, it is not known whether these findings are biological or clinically relevant in vivo (Rhodes et al., 2008), and one study showed the alterations were not statistically significant (Huang et al., 2021); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 29197658, 35508187, 33600800, 25637381, 19490272, 19716085, 17999538, 17470695, 17210839, 30420954, 32048431, 31043699, 30615648, 29501667, 18222468, 23465283) - |
Cardiac arrhythmia Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Nov 15, 2023 | This missense variant replaces isoleucine with valine at codon 274 of the KCNQ1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been performed for this variant. Whole-cell patch clamp experiments using transfected CHO cells have suggested that this variant may impact function (PMID: 18222468, 24920132). However, clinical relevance of these observations is not clear. This variant has been reported in individuals affected with sudden infant death syndrome (PMID: 17210839, 18222468) and long QT syndrome (PMID: 17470695). This variant has also been identified in 49/281866 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. - |
Short QT syndrome type 2 Benign:1
Benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Dec 12, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. - |
Cardiovascular phenotype Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 28, 2020 | 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. - |
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:17210839;PMID:19716085;PMID:17999538;PMID:17470695). 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