rs199473462
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_000218.3(KCNQ1):c.839T>A(p.Val280Glu) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,492 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. V280A) 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.839T>A | p.Val280Glu | missense_variant | 6/16 | ENST00000155840.12 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
KCNQ1 | ENST00000155840.12 | c.839T>A | p.Val280Glu | missense_variant | 6/16 | 1 | NM_000218.3 | P1 | |
KCNQ1 | ENST00000335475.6 | c.458T>A | p.Val153Glu | missense_variant | 6/16 | 1 | |||
KCNQ1 | ENST00000496887.7 | c.578T>A | p.Val193Glu | missense_variant | 7/16 | 5 | |||
KCNQ1 | ENST00000646564.2 | c.478-10531T>A | intron_variant |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461492Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1AN XY: 727062
GnomAD4 genome ? Cov.: 33
ClinVar
Submissions by phenotype
Long QT syndrome Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Mar 10, 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. 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: 53117). This missense change has been observed in individuals with long QT syndrome (PMID: 16414944, 19716085, 23158531; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces valine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 280 of the KCNQ1 protein (p.Val280Glu). - |
Cardiac arrhythmia Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Mar 07, 2023 | This missense variant replaces valine with glutamic acid at codon 280 of the KCNQ1 protein. This variant is found within a highly conserved region of the transmembrane domain S5. Rare nontruncating variants in this region have been shown to be significantly overrepresented in individuals with long QT syndrome (PMID: 32893267). A functional study has shown that this variant causes a large reduction of channel peak current density when expressed in Chinese hamster ovary cells (PMID: 34930020). This variant has been reported in at least three unrelated individuals affected with long QT syndrome (PMID: 16414944, 23158531, 32893267, 34930020, ClinVar SCV000074156.6) and in two individuals suspected of long QT syndrome (PMID: 19716085, 21956039). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely 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:16414944;PMID:19716085). 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