rs199472802
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1PM2PM5PP3_StrongPP5
The NM_000218.3(KCNQ1):c.1685G>T(p.Arg562Met) variant causes a missense, splice region 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. 3/3 splice prediction tools predicting alterations to normal splicing. 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. R562S) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000218.3 missense, splice_region
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 11 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
KCNQ1 | NM_000218.3 | c.1685G>T | p.Arg562Met | missense_variant, splice_region_variant | 13/16 | ENST00000155840.12 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
KCNQ1 | ENST00000155840.12 | c.1685G>T | p.Arg562Met | missense_variant, splice_region_variant | 13/16 | 1 | NM_000218.3 | P1 | |
KCNQ1 | ENST00000335475.6 | c.1304G>T | p.Arg435Met | missense_variant, splice_region_variant | 13/16 | 1 | |||
KCNQ1 | ENST00000496887.7 | c.1328G>T | p.Arg443Met | missense_variant, splice_region_variant | 13/16 | 5 | |||
KCNQ1 | ENST00000646564.2 | c.1145G>T | p.Arg382Met | missense_variant, splice_region_variant | 8/11 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0AN: 1402986Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 691954
GnomAD4 genome ? Cov.: 33
ClinVar
Submissions by phenotype
Long QT syndrome Pathogenic:1Uncertain:1
Likely pathogenic, criteria provided, single submitter | research | Dept of Medical Biology, Uskudar University | Jan 08, 2024 | Criteria: PS4_Moderate, PM5, PM2, PP3 - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jul 26, 2022 | This sequence change replaces arginine, which is basic and polar, with methionine, which is neutral and non-polar, at codon 562 of the KCNQ1 protein (p.Arg562Met). This variant also falls at the last nucleotide of exon 13, which is part of the consensus splice site for this exon. This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with long QT syndrome (PMID: 12566525, 22456477). ClinVar contains an entry for this variant (Variation ID: 67048). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). Experimental studies have shown that this missense change affects KCNQ1 function (PMID: 25037568). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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. - |
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: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