chr11-2445295-C-T

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

Scores

4
6
9

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2O:1

Conservation

PhyloP100: 0.0790
Variant links:
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
KCNQ1NM_000218.3 linkc.197C>T p.Ser66Phe missense_variant Exon 1 of 16 ENST00000155840.12 NP_000209.2 P51787-1Q96AI9
KCNQ1NM_001406836.1 linkc.197C>T p.Ser66Phe missense_variant Exon 1 of 15 NP_001393765.1
KCNQ1NM_001406838.1 linkc.197C>T p.Ser66Phe missense_variant Exon 1 of 11 NP_001393767.1
KCNQ1NM_001406837.1 linkc.-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
KCNQ1ENST00000155840.12 linkc.197C>T p.Ser66Phe missense_variant Exon 1 of 16 1 NM_000218.3 ENSP00000155840.2 P51787-1
KCNQ1ENST00000646564.2 linkc.197C>T p.Ser66Phe missense_variant Exon 1 of 11 ENSP00000495806.2 A0A2R8YEQ9
KCNQ1ENST00000496887.7 linkc.24-88C>T intron_variant Intron 1 of 15 5 ENSP00000434560.2 E9PPZ0
KCNQ1ENST00000345015.4 linkn.-27C>T upstream_gene_variant 1

Frequencies

GnomAD3 genomes
AF:
0.0000266
AC:
4
AN:
150588
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000970
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD4 exome
AF:
0.00000320
AC:
4
AN:
1250308
Hom.:
0
Cov.:
31
AF XY:
0.00000326
AC XY:
2
AN XY:
613288
show subpopulations
Gnomad4 AFR exome
AF:
0.0000387
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
9.87e-7
Gnomad4 OTH exome
AF:
0.0000392
GnomAD4 genome
AF:
0.0000265
AC:
4
AN:
150696
Hom.:
0
Cov.:
32
AF XY:
0.0000407
AC XY:
3
AN XY:
73654
show subpopulations
Gnomad4 AFR
AF:
0.0000967
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000302
ExAC
AF:
0.0000346
AC:
3

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
Jan 30, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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
Feb 19, 2021
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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
-
Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust
Significance: not provided
Review Status: no classification provided
Collection Method: literature only

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: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.13
BayesDel_addAF
Pathogenic
0.19
D
BayesDel_noAF
Uncertain
0.040
CADD
Benign
16
DANN
Benign
0.96
DEOGEN2
Uncertain
0.47
T
Eigen
Benign
-0.77
Eigen_PC
Benign
-0.83
FATHMM_MKL
Benign
0.059
N
LIST_S2
Benign
0.44
T
M_CAP
Pathogenic
0.89
D
MetaRNN
Uncertain
0.52
D
MetaSVM
Uncertain
0.64
D
MutationAssessor
Benign
1.0
L
PrimateAI
Pathogenic
0.84
D
PROVEAN
Benign
-2.0
N
REVEL
Pathogenic
0.65
Sift
Uncertain
0.0090
D
Sift4G
Uncertain
0.018
D
Polyphen
0.085
B
Vest4
0.24
MutPred
0.75
Loss of glycosylation at S66 (P = 4e-04);
MVP
0.94
MPC
1.5
ClinPred
0.21
T
GERP RS
2.0
Varity_R
0.079
gMVP
0.28

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs199473446; hg19: chr11-2466525; COSMIC: COSV105028162; COSMIC: COSV105028162; API