rs199472677

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 0P and 0B.

The NM_000218.3(KCNQ1):​c.328G>A​(p.Val110Ile) variant causes a missense change. The variant allele was found at a frequency of 0.0000632 in 1,597,702 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000085 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000061 ( 0 hom. )

Consequence

KCNQ1
NM_000218.3 missense

Scores

4
6
9

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6B:1O:1

Conservation

PhyloP100: 6.89
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 0 ACMG points.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
KCNQ1NM_000218.3 linkuse as main transcriptc.328G>A p.Val110Ile missense_variant 1/16 ENST00000155840.12 NP_000209.2 P51787-1Q96AI9
KCNQ1NM_001406836.1 linkuse as main transcriptc.328G>A p.Val110Ile missense_variant 1/15 NP_001393765.1
KCNQ1NM_001406838.1 linkuse as main transcriptc.328G>A p.Val110Ile missense_variant 1/11 NP_001393767.1
KCNQ1NM_001406837.1 linkuse as main transcriptc.-35G>A 5_prime_UTR_variant 1/17 NP_001393766.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
KCNQ1ENST00000155840.12 linkuse as main transcriptc.328G>A p.Val110Ile missense_variant 1/161 NM_000218.3 ENSP00000155840.2 P51787-1
KCNQ1ENST00000345015.4 linkuse as main transcriptn.105G>A non_coding_transcript_exon_variant 1/31
KCNQ1ENST00000496887.7 linkuse as main transcriptc.67G>A p.Val23Ile missense_variant 2/165 ENSP00000434560.2 E9PPZ0
KCNQ1ENST00000646564.2 linkuse as main transcriptc.328G>A p.Val110Ile missense_variant 1/11 ENSP00000495806.2 A0A2R8YEQ9

Frequencies

GnomAD3 genomes
AF:
0.0000855
AC:
13
AN:
152118
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
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:
0.000191
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000626
AC:
14
AN:
223660
Hom.:
0
AF XY:
0.0000726
AC XY:
9
AN XY:
124044
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.000105
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000129
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000609
AC:
88
AN:
1445584
Hom.:
0
Cov.:
31
AF XY:
0.0000653
AC XY:
47
AN XY:
719546
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.0000383
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000765
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
AF:
0.0000855
AC:
13
AN:
152118
Hom.:
0
Cov.:
32
AF XY:
0.0000807
AC XY:
6
AN XY:
74306
show subpopulations
Gnomad4 AFR
AF:
0.00
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:
0.000191
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000136
Hom.:
0
Bravo
AF:
0.0000907
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000235
AC:
2
ExAC
AF:
0.0000842
AC:
10
EpiCase
AF:
0.000218
EpiControl
AF:
0.000415

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:6Benign:1Other:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Uncertain:2Benign:1Other:1
Uncertain significance, criteria provided, single submitterclinical testingGeneDxNov 19, 2024Identified in a patient with LQTS in published literature; however, this patient harbored an additional variant in the KCNH2 gene (PMID: 21164565); Identified in two cases of stillbirth in published literature (PMID: 30615648); Published functional studies suggest a damaging effect via decreased current density and prolonged duration of simulated left ventricular epicardial action potentials, but without affecting cell surface expression (PMID: 30571187, 21164565, 29532034); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 14661677, 21164565, 23861362, 22949429, 19841300, 30571187, 29532034, 29021305, 32797034, 22581653, 30615648) -
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:14661677;PMID:19841300;PMID:21164565). -
Likely benign, criteria provided, single submitterresearchBiesecker Lab/Clinical Genomics Section, National Institutes of HealthJun 24, 2013- -
Uncertain significance, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenMay 01, 2018- -
Long QT syndrome 1 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingVictorian Clinical Genetics Services, Murdoch Childrens Research InstituteJun 24, 2022Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3B. Following criteria are met: 0103 - Dominant negative, loss of function and gain of function are known mechanisms of disease in this gene. Gain of function variants result exclusively in short QT syndrome (MIM#609621), while dominant negative and loss of function variants can cause long QT syndrome (LQTS, MIM#192500), atrial fibrillation (MIM#607554) and Jervell and Lange-Nielsen syndrome (JLNS, MIM#220400) (OMIM, PMIDs: 19632626, 28438721). (I) 0108 - This gene is known to be associated with both recessive and dominant disease. JLNS is characterized by congenital, bilateral deafness and variable degrees of QT prolongation, and is the only condition caused by biallelic variants (PMID: 28438721). (I) 0112 - The condition associated with this gene has incomplete penetrance (OMIM, GeneReviews). (I) 0200 - Variant is predicted to result in a missense amino acid change from valine to isoleucine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2 and v3) <0.01 for a condition (27 heterozygotes, 0 homozygotes). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0808 - Previous reports of pathogenicity for this variant are conflicting. This variant has been classified as a VUS by multiple clinical diagnostic laboratories and a benign variant based on its allele frequency being greater than published estimates for LQTS disease prevalence (ClinVar, PMID: 23861362). However, this variant has also been reported in two stillbirth cases and one individual with severe LQTS who carried an additional common polymorphism in KCNH2 (PMIDs: 30615648, 21164565). (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1002 - This variant has moderate functional evidence supporting abnormal protein function. The mutant transcript expressed in both CHO-KI and HEK293T cells and assessed using patch clamp studies demonstrated normal surface trafficking levels but reduced peak current densities compared to the WT transcript (PMIDs: 21164565, 29532034). It should be noted that the same reduction in peak current density was also observed in CHO-KI cells carrying a KCNH2 common polymorphism (PMID: 21164565). (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineJun 02, 2015The p.Val110Ile variant in KCNQ1 has not been previously reported in individuals with hearing loss or Jervell and Lange-Nielsen syndrome; however, it has been i dentified in one individual with long QT syndrome (Cordeiro 2010). This variant has also been identified in 8/55006 European chromosomes by the Exome Aggregatio n Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs199472677). In vitro functional studies provide some evidence that this variant may impact protein f unction (Cordeiro 2010); however, these types of assays may not accurately repre sent biological function. Computational prediction tools and conservation analy ses suggest that the p.Val110Ile variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. In summary, the clinical significance of the p.Val110Ile variant is uncertain. -
Long QT syndrome Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpDec 06, 2023This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 110 of the KCNQ1 protein (p.Val110Ile). This variant is present in population databases (rs199472677, gnomAD 0.01%). This missense change has been observed in individual(s) with long QT syndrome (PMID: 14661677, 19841300, 21164565). ClinVar contains an entry for this variant (Variation ID: 53034). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on KCNQ1 protein function. Experimental studies have shown that this missense change affects KCNQ1 function (PMID: 21164565, 29532034). 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 submitterclinical testingAmbry GeneticsFeb 18, 2022The c.328G>A (p.V110I) alteration is located in exon 1 (coding exon 1) of the KCNQ1 gene. This alteration results from a G to A substitution at nucleotide position 328, causing the valine (V) at amino acid position 110 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.15
BayesDel_addAF
Uncertain
0.023
T
BayesDel_noAF
Uncertain
0.040
CADD
Uncertain
25
DANN
Uncertain
0.99
DEOGEN2
Benign
0.31
.;T
Eigen
Benign
-0.036
Eigen_PC
Benign
0.067
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Uncertain
0.97
D;D
M_CAP
Pathogenic
0.76
D
MetaRNN
Uncertain
0.50
T;T
MetaSVM
Pathogenic
1.3
D
MutationAssessor
Benign
1.6
.;L
PrimateAI
Pathogenic
0.84
D
PROVEAN
Benign
-0.36
N;N
REVEL
Uncertain
0.56
Sift
Benign
0.42
T;T
Sift4G
Benign
0.29
T;T
Polyphen
0.21
.;B
Vest4
0.28
MVP
0.93
MPC
0.95
ClinPred
0.20
T
GERP RS
3.0
Varity_R
0.13
gMVP
0.73

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: rs199472677; hg19: chr11-2466656; API