rs199472748
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_000218.3(KCNQ1):c.941G>A(p.Gly314Asp) 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. 12/21 in silico tools predict a damaging 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. G314A) 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.941G>A | p.Gly314Asp | missense_variant | 7/16 | ENST00000155840.12 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
KCNQ1 | ENST00000155840.12 | c.941G>A | p.Gly314Asp | missense_variant | 7/16 | 1 | NM_000218.3 | P1 | |
KCNQ1 | ENST00000335475.6 | c.560G>A | p.Gly187Asp | missense_variant | 7/16 | 1 | |||
KCNQ1 | ENST00000496887.7 | c.680G>A | p.Gly227Asp | missense_variant | 8/16 | 5 | |||
KCNQ1 | ENST00000646564.2 | c.497G>A | p.Gly166Asp | missense_variant | 3/11 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD4 exome Cov.: 31
GnomAD4 genome ? Cov.: 33
ClinVar
Submissions by phenotype
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Oct 03, 2023 | Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 15466642, 23995044, 22949429, 15840476, 23124029, 29654130, 32168391, 32421437) - |
Long QT syndrome Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jun 07, 2022 | This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 314 of the KCNQ1 protein (p.Gly314Asp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with long QT syndrome (PMID: 22949429, 32168391). ClinVar contains an entry for this variant (Variation ID: 53138). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. This variant disrupts the p.Gly314 amino acid residue in KCNQ1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 8872472, 9799083, 16922724, 22727609, 22949429). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. - |
Cardiovascular phenotype Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 01, 2019 | The p.G314D pathogenic mutation (also known as c.941G>A), located in coding exon 7 of the KCNQ1 gene, results from a G to A substitution at nucleotide position 941. The glycine at codon 314 is replaced by aspartic acid, an amino acid with similar properties, and is located in the ion selectivity filter (GYGD) motif of the intramembrane pore-forming region between transmembrane helices S5 and S6. This alteration has been reported in patients with long QT syndrome (LQTS), including a proband identified in utero with fetal bradycardia and 2nd degree AV block (Choi G et al. Circulation. 2004;110:2119-24; Mitchell JL et al. Circulation. 2012;126:2688-95). Several alterations impacting this amino acid have been identified in multiple patients with LQTS; and one (p.G314S, c.940G>A) has been reported to co-segregate with disease in multiple families and has demonstrated significantly reduced IKs current density in heterologous expression studies (Russell MW et al. Hum. Mol. Genet. 1996;5:1319-24; Chouabe C et al. EMBO J. 1997;16:5472-9). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. - |
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:12566525;PMID:15466642;PMID:15840476;PMID:19841300). 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