11-2572979-G-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1PM2PM5PP3_StrongPP5

The NM_000218.3(KCNQ1):​c.914G>T​(p.Trp305Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,460,482 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. W305R) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 33)
Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

KCNQ1
NM_000218.3 missense

Scores

14
4
1

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:6U:2

Conservation

PhyloP100: 9.36
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 Pathogenic. Variant got 11 ACMG points.

PM1
In a intramembrane_region Pore-forming; Name=Segment H5 (size 20) in uniprot entity KCNQ1_HUMAN there are 54 pathogenic changes around while only 0 benign (100%) in NM_000218.3
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr11-2572978-T-C is described in Lovd as [Pathogenic].
PP3
MetaRNN computational evidence supports a deleterious effect, 0.988
PP5
Variant 11-2572979-G-T is Pathogenic according to our data. Variant chr11-2572979-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 200824.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=2, Pathogenic=3, Likely_pathogenic=3}. Variant chr11-2572979-G-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
KCNQ1NM_000218.3 linkc.914G>T p.Trp305Leu missense_variant Exon 6 of 16 ENST00000155840.12 NP_000209.2 P51787-1Q96AI9

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
KCNQ1ENST00000155840.12 linkc.914G>T p.Trp305Leu missense_variant Exon 6 of 16 1 NM_000218.3 ENSP00000155840.2 P51787-1
KCNQ1ENST00000335475.6 linkc.533G>T p.Trp178Leu missense_variant Exon 6 of 16 1 ENSP00000334497.5 P51787-2
KCNQ1ENST00000496887.7 linkc.653G>T p.Trp218Leu missense_variant Exon 7 of 16 5 ENSP00000434560.2 E9PPZ0
KCNQ1ENST00000646564.2 linkc.478-10456G>T intron_variant Intron 2 of 10 ENSP00000495806.2 A0A2R8YEQ9

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD3 exomes
AF:
0.00000401
AC:
1
AN:
249180
Hom.:
0
AF XY:
0.00000740
AC XY:
1
AN XY:
135116
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:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.000165
GnomAD4 exome
AF:
0.00000205
AC:
3
AN:
1460482
Hom.:
0
Cov.:
32
AF XY:
0.00000138
AC XY:
1
AN XY:
726452
show subpopulations
Gnomad4 AFR exome
AF:
0.00
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:
0.00000180
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
Cov.:
33
ExAC
AF:
0.00000824
AC:
1

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:6Uncertain:2
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Long QT syndrome 1 Pathogenic:3
Pathogenic, criteria provided, single submitterclinical testingInstitute of Human Genetics, University of Leipzig Medical CenterJan 01, 2019- -
Likely pathogenic, criteria provided, single submitterclinical testingVictorian Clinical Genetics Services, Murdoch Childrens Research InstituteOct 19, 2020Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as Likely pathogenic. 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 mutations result exclusively in short QT syndrome (MIM#609621), while dominant negative and loss of function mutations 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) (N) 0112 - Variants in this gene are known to have reduced penetrance (PMID: 20301308, OMIM). (N) 0200 - Variant is predicted to result in a missense amino acid change from tryptophan to leucine (exon 6). (N) 0251 - Variant is heterozygous. (N) 0302 - Variant is present in gnomAD <0.001 for a dominant condition (v2: 1 heterozygote, 0 homozygotes). (P) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2: 1 heterozygote, 0 homozygotes). (N) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (P) 0600 - Variant is located in an annotated domain or motif. The variant is located in the P-loop region of the KCNQ1 gene (PMID: 26344792). (N) 0703 - Comparable variants have moderate previous evidence for pathogenicity. The p.W305S, p.W305R and p.W305C comparable variants have been described in multiple individuals with LQTS or JLNS (PMIDs: 1584047; 9781056; 23158531; 22456477). (P) 0802 - Moderate previous evidence of pathogenicity in unrelated individuals. This variant has been reported in four unrelated individuals with LQTS (ClinVar; PMIDs: 26344792; 28532774). (P) 1002 - Limited functional evidence supporting abnormal protein function. Using whole-cell patch clamp technique, the p.W305L mutant cDNA transfected into COS-7 monkey kidney cells demonstrated reduced Kv7.1 channel peak current density compared to COS-7 cells transfected with WT cDNA. However, patch clamp assays have been shown to be unreliable, therefore results from these studies are used with caution during variant classification (PMID: 26344792). (N) 1208 - Inherited information for this variant is not currently available. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign -
Pathogenic, criteria provided, single submitterclinical testingCenter For Human Genetics And Laboratory Diagnostics, Dr. Klein, Dr. Rost And ColleaguesApr 20, 2018- -
Long QT syndrome Pathogenic:1Uncertain:1
Likely pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpMar 11, 2024This sequence change replaces tryptophan, which is neutral and slightly polar, with leucine, which is neutral and non-polar, at codon 305 of the KCNQ1 protein (p.Trp305Leu). This variant is present in population databases (rs120074186, gnomAD no frequency). This missense change has been observed in individual(s) with long QT syndrome (PMID: 26344792). ClinVar contains an entry for this variant (Variation ID: 200824). 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 with a positive predictive value of 95%. Experimental studies have shown that this missense change affects KCNQ1 function (PMID: 26344792). This variant disrupts the p.Trp305 amino acid residue in KCNQ1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 19490272, 19716085, 21451124, 26344792). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. -
Uncertain significance, criteria provided, single submitterclinical testingAll of Us Research Program, National Institutes of HealthFeb 05, 2024This missense variant replaces tryptophan with leucine at codon 305 of the KCNQ1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). This variant is found within a highly conserved pore region (a.a. 300-320). Rare non-truncating 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 results in significantly decreased peak current densities compared to wild type protein (PMID: 26344792). This variant has been reported in 2 individuals affected with long QT syndrome (PMID: 26344792, 28532774) and 2 individuals with suspected long QT syndrome (PMID: 31737537). This variant was found to partially segregate in a family with long QT syndrome and a syncope phenotype (PMID: 26344792). A different missense variant occurring at the same codon, p.Trp305Ser, is known to be disease-causing (ClinVar variation ID: 3127). This variant has been identified in 1/249180 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Although there is a suspicion for a pathogenic role, the available evidence is insufficient to determine the role of this p.Trp305Leu variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
Jervell and Lange-Nielsen syndrome 1 Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testing3billion, Medical GeneticsJan 03, 2022Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000200824, PMID:26344792, PS1_S). Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID:26344792, PS3_S). A different missense change at the same codon has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000003127, PMID:9781056,19716085, PM5_M). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000004, PM2_M). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.97, 3CNET: 0.999, PP3_P). A missense variant is a common mechanism associated with Jervell and Lange-Nielsen syndrome (PP2_P).Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitterclinical testingGeneDxAug 16, 2022Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies demonstrate a damaging effect of the potassium ion channel function, with reduced peak current density in transfected COS7 cells (Zhou et al., 2015); This variant is associated with the following publications: (PMID: 26344792, 28532774, 31737537, 32431610, 34428338) -
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsJan 24, 2022The p.W305L variant (also known as c.914G>T), located in coding exon 6 of the KCNQ1 gene, results from a G to T substitution at nucleotide position 914. The tryptophan at codon 305 is replaced by leucine, an amino acid with similar properties. This variant has been detected in an individual with long QT syndrome (LQTS) and in relatives with normal QTc intervals (Zhou H et al. Cardiol Young, 2016 Apr;26:754-63). This variant was also detected in an individual with prolonged QTc in the setting of congenital heart disease, and in individuals referred for LQTS genetic testing for whom clinical details were limited (Ebrahim MA et al. Am. J. Cardiol., 2017 Jul;120:256-261; Marschall C et al. Cardiovasc Diagn Ther, 2019 Oct;9:S292-S298). This variant was also detected in a genome sequencing cohort in individuals with normal ECGs or who were not indicated as having LQTS on ECG (Elfatih A et al. Hum Mutat, 2021 Aug). In one in vitro study, this variant resulted in reduced current density compared to wild type when expressed in the mock-homozygous state (Zhou H et al. Cardiol Young, 2016 Apr;26:754-63). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.99
BayesDel_addAF
Pathogenic
0.57
D
BayesDel_noAF
Pathogenic
0.58
CADD
Pathogenic
33
DANN
Uncertain
0.99
DEOGEN2
Pathogenic
0.99
D;.
Eigen
Pathogenic
0.74
Eigen_PC
Uncertain
0.66
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Pathogenic
0.99
D;D
M_CAP
Pathogenic
0.95
D
MetaRNN
Pathogenic
0.99
D;D
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Pathogenic
3.8
H;.
PrimateAI
Uncertain
0.74
T
PROVEAN
Pathogenic
-13
D;D
REVEL
Pathogenic
0.97
Sift
Uncertain
0.0010
D;D
Sift4G
Pathogenic
0.0
D;D
Polyphen
1.0
D;D
Vest4
0.99
MutPred
0.86
Loss of helix (P = 0.0376);.;
MVP
0.99
MPC
1.6
ClinPred
1.0
D
GERP RS
3.9
Varity_R
0.99
gMVP
0.99

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.030
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: rs120074186; hg19: chr11-2594209; API