chr11-2570671-G-T
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_000218.3(KCNQ1):c.521G>T(p.Arg174Leu) 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. R174C) has been classified as Likely pathogenic.
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.521G>T | p.Arg174Leu | missense_variant | 3/16 | ENST00000155840.12 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
KCNQ1 | ENST00000155840.12 | c.521G>T | p.Arg174Leu | missense_variant | 3/16 | 1 | NM_000218.3 | P1 | |
KCNQ1 | ENST00000335475.6 | c.140G>T | p.Arg47Leu | missense_variant | 3/16 | 1 | |||
KCNQ1 | ENST00000496887.7 | c.260G>T | p.Arg87Leu | missense_variant | 4/16 | 5 | |||
KCNQ1 | ENST00000646564.2 | c.478-12764G>T | intron_variant |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0AN: 1460214Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 726504
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
Long QT syndrome 1 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Molecular Genetics Laboratory - Cardiogenetics, CHU de Nantes | Aug 01, 2023 | - - |
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jun 17, 2014 | The R174L mutation in the KCNQ1 gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. However, other mutations affecting the same residue (R174C, R174H, R174P), as well as mutations affecting nearby residues (V172M, V173D, A178P) have been reported in HGMD in association with LQTS (Stenson P et al., 2009), supporting the functional importance of this residue and this region of the protein. R174L results in a non-conservative amino acid substitution of a positively charged Arginine residue with a non-polar Leucine residue. In silico analysis predicts R174L is probably damaging to the protein structure/function. Furthermore, R174L was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. In summary, R174L in the KCNQ1 gene is interpreted as a likely disease-causing mutation - |
Long QT syndrome Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Aug 03, 2023 | 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. This variant disrupts the p.Arg174 amino acid residue in KCNQ1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9386136, 14998624, 23130128, 23392653, 29532034). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects KCNQ1 function (PMID: 29532034, 30571187). 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 expected to disrupt KCNQ1 protein function. ClinVar contains an entry for this variant (Variation ID: 200814). This missense change has been observed in individual(s) with long-QT syndrome (PMID: 21956039). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 174 of the KCNQ1 protein (p.Arg174Leu). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at