rs199472762
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_000218.3(KCNQ1):c.1027C>T(p.Pro343Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P343L) has been classified as Uncertain significance.
Frequency
Consequence
NM_000218.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
KCNQ1 | NM_000218.3 | c.1027C>T | p.Pro343Ser | missense_variant | 7/16 | ENST00000155840.12 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
KCNQ1 | ENST00000155840.12 | c.1027C>T | p.Pro343Ser | missense_variant | 7/16 | 1 | NM_000218.3 | P1 | |
KCNQ1 | ENST00000335475.6 | c.646C>T | p.Pro216Ser | missense_variant | 7/16 | 1 | |||
KCNQ1 | ENST00000496887.7 | c.766C>T | p.Pro256Ser | missense_variant | 8/16 | 5 | |||
KCNQ1 | ENST00000646564.2 | c.583C>T | p.Pro195Ser | missense_variant | 3/11 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD4 exome Cov.: 30
GnomAD4 genome ? Cov.: 33
ClinVar
Submissions by phenotype
Long QT syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Sep 08, 2020 | This sequence change replaces proline with serine at codon 343 of the KCNQ1 protein (p.Pro343Ser). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and serine. This variant is not present in population databases (ExAC no frequency). This variant has been observed to segregate with long QT syndrome in a family and has been reported in individuals affected with long QT syndrome (PMID: 15511625, 15840476, Invitae). ClinVar contains an entry for this variant (Variation ID: 52933). This variant has been reported to affect KCNQ1 protein function (PMID: 15511625). This variant disrupts the p.Pro343 amino acid residue in KCNQ1. Other variant(s) that disrupt this residue have been observed in individuals with KCNQ1-related conditions (PMID: 22949429, 16414944), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. - |
Cardiovascular phenotype Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 27, 2023 | The p.P343S variant (also known as c.1027C>T), located in coding exon 7 of the KCNQ1 gene, results from a C to T substitution at nucleotide position 1027. The proline at codon 343 is replaced by serine, an amino acid with similar properties. This variant has been detected in individuals reported to have long QT syndrome (LQTS) or presentations consistent with LQTS, and segregated with disease in a family (Choi G et al. Circulation, 2004 Oct;110:2119-24; Tester DJ et al. Heart Rhythm, 2005 May;2:507-17; Moss AJ et al. Circulation, 2007 May;115:2481-9; Zehelein J et al. Biochim Biophys Acta, 2004 Nov;1690:185-92; external communication; Ambry internal data). In vitro functional studies by one group have indicated that this variant results in reduced channel current (Zehelein J et al. Biochim Biophys Acta, 2004 Nov;1690:185-92). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. - |
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:15466642;PMID:15511625;PMID:15840476;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