11-2445295-C-T
Variant names:
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 0P and 0B.
The NM_000218.3(KCNQ1):c.197C>T(p.Ser66Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000571 in 1,401,004 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: 𝑓 0.000027 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000032 ( 0 hom. )
Consequence
KCNQ1
NM_000218.3 missense
NM_000218.3 missense
Scores
4
6
9
Clinical Significance
Conservation
PhyloP100: 0.0790
Genes affected
KCNQ1 (HGNC:6294): (potassium voltage-gated channel subfamily Q member 1) This gene encodes a voltage-gated potassium channel required for repolarization phase of the cardiac action potential. This protein can form heteromultimers with two other potassium channel proteins, KCNE1 and KCNE3. Mutations in this gene are associated with hereditary long QT syndrome 1 (also known as Romano-Ward syndrome), Jervell and Lange-Nielsen syndrome, and familial atrial fibrillation. This gene exhibits tissue-specific imprinting, with preferential expression from the maternal allele in some tissues, and biallelic expression in others. This gene is located in a region of chromosome 11 amongst other imprinted genes that are associated with Beckwith-Wiedemann syndrome (BWS), and itself has been shown to be disrupted by chromosomal rearrangements in patients with BWS. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Aug 2011]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 0 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
KCNQ1 | NM_000218.3 | c.197C>T | p.Ser66Phe | missense_variant | Exon 1 of 16 | ENST00000155840.12 | NP_000209.2 | |
KCNQ1 | NM_001406836.1 | c.197C>T | p.Ser66Phe | missense_variant | Exon 1 of 15 | NP_001393765.1 | ||
KCNQ1 | NM_001406838.1 | c.197C>T | p.Ser66Phe | missense_variant | Exon 1 of 11 | NP_001393767.1 | ||
KCNQ1 | NM_001406837.1 | c.-166C>T | 5_prime_UTR_variant | Exon 1 of 17 | NP_001393766.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
KCNQ1 | ENST00000155840.12 | c.197C>T | p.Ser66Phe | missense_variant | Exon 1 of 16 | 1 | NM_000218.3 | ENSP00000155840.2 | ||
KCNQ1 | ENST00000646564.2 | c.197C>T | p.Ser66Phe | missense_variant | Exon 1 of 11 | ENSP00000495806.2 | ||||
KCNQ1 | ENST00000496887.7 | c.24-88C>T | intron_variant | Intron 1 of 15 | 5 | ENSP00000434560.2 | ||||
KCNQ1 | ENST00000345015.4 | n.-27C>T | upstream_gene_variant | 1 |
Frequencies
GnomAD3 genomes AF: 0.0000266 AC: 4AN: 150588Hom.: 0 Cov.: 32
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GnomAD4 exome AF: 0.00000320 AC: 4AN: 1250308Hom.: 0 Cov.: 31 AF XY: 0.00000326 AC XY: 2AN XY: 613288
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GnomAD4 genome AF: 0.0000265 AC: 4AN: 150696Hom.: 0 Cov.: 32 AF XY: 0.0000407 AC XY: 3AN XY: 73654
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:2Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Long QT syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 30, 2025 | This sequence change replaces serine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 66 of the KCNQ1 protein (p.Ser66Phe). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of long QT syndrome (PMID: 19716085). ClinVar contains an entry for this variant (Variation ID: 67063). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt KCNQ1 protein function with a negative predictive value of 95%. Experimental studies have shown that this missense change affects KCNQ1 function (PMID: 34930020). 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. - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 19, 2021 | The c.197C>T (p.S66F) alteration is located in exon 1 (coding exon 1) of the KCNQ1 gene. This alteration results from a C to T substitution at nucleotide position 197, causing the serine (S) at amino acid position 66 to be replaced by a phenylalanine (F). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
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: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:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Uncertain
CADD
Benign
DANN
Benign
DEOGEN2
Uncertain
T
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Benign
N
LIST_S2
Benign
T
M_CAP
Pathogenic
D
MetaRNN
Uncertain
D
MetaSVM
Uncertain
D
MutationAssessor
Benign
L
PrimateAI
Pathogenic
D
PROVEAN
Benign
N
REVEL
Pathogenic
Sift
Uncertain
D
Sift4G
Uncertain
D
Polyphen
B
Vest4
MutPred
Loss of glycosylation at S66 (P = 4e-04);
MVP
MPC
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at