rs775608046
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate
The NM_000218.3(KCNQ1):c.1885G>A(p.Gly629Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000381 in 1,574,258 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 Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G629V) has been classified as Uncertain significance.
Frequency
Consequence
NM_000218.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
KCNQ1 | NM_000218.3 | c.1885G>A | p.Gly629Ser | missense_variant | 16/16 | ENST00000155840.12 | |
KCNQ1-AS1 | NR_130721.1 | n.778-7415C>T | intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
KCNQ1 | ENST00000155840.12 | c.1885G>A | p.Gly629Ser | missense_variant | 16/16 | 1 | NM_000218.3 | P1 | |
KCNQ1-AS1 | ENST00000440887.2 | n.777-7415C>T | intron_variant, non_coding_transcript_variant | 5 |
Frequencies
GnomAD3 genomes ? AF: 0.0000460 AC: 7AN: 152148Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000490 AC: 9AN: 183736Hom.: 0 AF XY: 0.0000604 AC XY: 6AN XY: 99376
GnomAD4 exome AF: 0.0000373 AC: 53AN: 1422110Hom.: 0 Cov.: 31 AF XY: 0.0000355 AC XY: 25AN XY: 703746
GnomAD4 genome ? AF: 0.0000460 AC: 7AN: 152148Hom.: 0 Cov.: 33 AF XY: 0.0000538 AC XY: 4AN XY: 74334
ClinVar
Submissions by phenotype
Long QT syndrome Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Aug 27, 2021 | This sequence change replaces glycine with serine at codon 629 of the KCNQ1 protein (p.Gly629Ser). The glycine residue is weakly conserved and there is a small physicochemical difference between glycine and serine. This variant is present in population databases (rs775608046, ExAC 0.04%). This missense change has been observed in individual(s) with long QT syndrome (PMID: 27871843). ClinVar contains an entry for this variant (Variation ID: 427960). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The serine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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 | Feb 05, 2024 | This missense variant replaces glycine with serine at codon 629 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 affected with long QT syndrome (PMID 27871843), Brugada syndrome (PMID: 29255176), or hypertrophic cardiomyopathy (PMID: 25351510). This variant has been identified in 11/215064 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. - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | May 23, 2019 | The KCNQ1 c.1885G>A; p.Gly629Ser variant (rs775608046) is reported in the literature in an individual affected with long QT syndrome, though it was not demonstrated to be disease-causing (Chae 2017). This variant is found in the general population with a low overall allele frequency of 0.005% (11/215064 alleles) in the Genome Aggregation Database. The glycine at codon 629 is weakly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is tolerated. However, due to limited information, the clinical significance of the p.Gly629Ser variant is uncertain at this time. References: Chae H et al. Considerations when using next-generation sequencing for genetic diagnosis of long-QT syndrome in the clinical testing laboratory. Clin Chim Acta. 2017 Jan;464:128-135. - |
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 | Dec 08, 2021 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jun 27, 2019 | Reported in association with hypertrophic cardiomyopathy, Brugada syndrome, and LQTS (Lopes et al., 2015; Robyns et al., 2017; Chae et al., 2017); Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 427960; Landrum et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 27871843, 25351510, 29255176) - |
Brugada syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Center for Human Genetics, University of Leuven | Apr 30, 2017 | - - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 26, 2023 | The p.G629S variant (also known as c.1885G>A), located in coding exon 16 of the KCNQ1 gene, results from a G to A substitution at nucleotide position 1885. The glycine at codon 629 is replaced by serine, an amino acid with similar properties. This alteration was reported in one patient with long QT syndrome, though specific clinical details were limited (Chae H et al. Clin Chim Acta, 2017 Jan;464:128-135). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Cardiac arrhythmia Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Jul 28, 2023 | This missense variant replaces glycine with serine at codon 629 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 affected with long QT syndrome (PMID 27871843), Brugada syndrome (PMID: 29255176), or hypertrophic cardiomyopathy (PMID: 25351510). This variant has been identified in 11/215064 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at