rs199473465

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM5BP4

The NM_000218.3(KCNQ1):​c.878G>A​(p.Arg293His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000123 in 1,461,470 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. 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. R293C) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 33)
Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

KCNQ1
NM_000218.3 missense

Scores

1
7
11

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5B:1O:1

Conservation

PhyloP100: -0.0700
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM5
Other missense variant is known to change same aminoacid residue: Variant chr11-2572942-C-T is described in Lovd as [Pathogenic].
BP4
Computational evidence support a benign effect (MetaRNN=0.2719402).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
KCNQ1NM_000218.3 linkuse as main transcriptc.878G>A p.Arg293His missense_variant 6/16 ENST00000155840.12 NP_000209.2 P51787-1Q96AI9

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
KCNQ1ENST00000155840.12 linkuse as main transcriptc.878G>A p.Arg293His missense_variant 6/161 NM_000218.3 ENSP00000155840.2 P51787-1
KCNQ1ENST00000335475.6 linkuse as main transcriptc.497G>A p.Arg166His missense_variant 6/161 ENSP00000334497.5 P51787-2
KCNQ1ENST00000496887.7 linkuse as main transcriptc.617G>A p.Arg206His missense_variant 7/165 ENSP00000434560.2 E9PPZ0
KCNQ1ENST00000646564.2 linkuse as main transcriptc.478-10492G>A intron_variant ENSP00000495806.2 A0A2R8YEQ9

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD3 exomes
AF:
0.0000160
AC:
4
AN:
250276
Hom.:
0
AF XY:
0.0000147
AC XY:
2
AN XY:
135622
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000653
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000177
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000123
AC:
18
AN:
1461470
Hom.:
0
Cov.:
32
AF XY:
0.0000110
AC XY:
8
AN XY:
727048
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000224
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000812
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000809
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
Cov.:
33
Bravo
AF:
0.00000378
ExAC
AF:
0.00000824
AC:
1
Asia WGS
AF:
0.000289
AC:
1
AN:
3478
EpiCase
AF:
0.000109
EpiControl
AF:
0.00

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:5Benign:1Other:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Long QT syndrome Uncertain:2
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpAug 06, 2022This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 293 of the KCNQ1 protein (p.Arg293His). This variant is present in population databases (rs199473465, gnomAD 0.006%). This variant has not been reported in the literature in individuals affected with KCNQ1-related conditions. ClinVar contains an entry for this variant (Variation ID: 67118). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The histidine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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. -
Uncertain significance, criteria provided, single submitterclinical testingAll of Us Research Program, National Institutes of HealthDec 01, 2023This missense variant replaces arginine with histidine at codon 293 of the KCNQ1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an unaffected control individual in a long QT syndrome case-control study (PMID:19841300). This variant has been identified in 4/250276 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
Long QT syndrome 1 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingCenter For Human Genetics And Laboratory Diagnostics, Dr. Klein, Dr. Rost And ColleaguesApr 15, 2020- -
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsJan 12, 2022The c.878G>A (p.R293H) alteration is located in exon 6 (coding exon 6) of the KCNQ1 gene. This alteration results from a G to A substitution at nucleotide position 878, causing the arginine (R) at amino acid position 293 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -
Cardiac arrhythmia Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingColor Diagnostics, LLC DBA Color HealthMay 01, 2023This missense variant replaces arginine with histidine at codon 293 of the KCNQ1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an unaffected control individual in a long QT syndrome case-control study (PMID:19841300). This variant has been identified in 4/250276 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
not specified Benign:1
Likely benign, criteria provided, single submitterclinical testingGeneDxAug 19, 2011This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
not provided Other:1
not provided, no classification providedliterature onlyCardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust-This variant has been reported in the following publications (PMID:19841300). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.066
BayesDel_addAF
Benign
0.0014
T
BayesDel_noAF
Uncertain
-0.050
CADD
Benign
12
DANN
Uncertain
0.99
DEOGEN2
Pathogenic
0.87
D;.
Eigen
Benign
-1.0
Eigen_PC
Benign
-1.2
FATHMM_MKL
Benign
0.019
N
LIST_S2
Benign
0.68
T;T
M_CAP
Uncertain
0.28
D
MetaRNN
Benign
0.27
T;T
MetaSVM
Uncertain
0.48
D
MutationAssessor
Benign
0.66
N;.
PrimateAI
Benign
0.30
T
PROVEAN
Benign
-2.3
N;N
REVEL
Uncertain
0.52
Sift
Uncertain
0.0070
D;D
Sift4G
Uncertain
0.029
D;D
Polyphen
0.83
P;P
Vest4
0.30
MutPred
0.48
Gain of disorder (P = 0.1129);.;
MVP
0.80
MPC
0.47
ClinPred
0.091
T
GERP RS
-3.1
Varity_R
0.19
gMVP
0.83

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: rs199473465; hg19: chr11-2594173; COSMIC: COSV50105016; COSMIC: COSV50105016; API