11-2572979-G-T

Position:

chr11-2572979-G-T

Variant summary

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

The ENST00000155840.12(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 Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

KCNQ1
ENST00000155840.12 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5U:3

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]

KCNQ1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 11 ACMG points.

PM1

In a hotspot region, there are 11 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 14 uncertain in ENST00000155840.12

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr11-2572979-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 3127.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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: {Likely_pathogenic=2, Pathogenic=3, Uncertain_significance=3}. Variant chr11-2572979-G-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNQ1	NM_000218.3 linkuse as main transcript	c.914G>T	p.Trp305Leu	missense_variant	6/16	ENST00000155840.12	NP_000209.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNQ1	ENST00000155840.12 linkuse as main transcript	c.914G>T	p.Trp305Leu	missense_variant	6/16	1	NM_000218.3	ENSP00000155840	P1	P51787-1
KCNQ1	ENST00000335475.6 linkuse as main transcript	c.533G>T	p.Trp178Leu	missense_variant	6/16	1		ENSP00000334497		P51787-2
KCNQ1	ENST00000496887.7 linkuse as main transcript	c.653G>T	p.Trp218Leu	missense_variant	7/16	5		ENSP00000434560
KCNQ1	ENST00000646564.2 linkuse as main transcript	c.478-10456G>T		intron_variant				ENSP00000495806

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000401

AC:

AN:

249180

Hom.:

AF XY:

0.00000740

AC XY:

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:

AN:

1460482

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

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.:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:5Uncertain:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Long QT syndrome 1

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Center For Human Genetics And Laboratory Diagnostics, Dr. Klein, Dr. Rost And Colleagues	Apr 20, 2018	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Oct 19, 2020	Based 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 submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Jan 01, 2019	- -

Long QT syndrome

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	May 09, 2022	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. 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. Experimental studies have shown that this missense change affects KCNQ1 function (PMID: 26344792). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. This 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). -
Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Feb 05, 2024	This 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 submitter

clinical testing

3billion

Jan 03, 2022

Same 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 submitter

clinical testing

GeneDx

Aug 16, 2022

Not 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 submitter

clinical testing

Ambry Genetics

Jan 24, 2022

The 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

BayesDel_noAF

Pathogenic

0.58

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.99

D;.

Eigen

Pathogenic

0.74

Eigen_PC

Uncertain

0.66

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.99

D;D

M_CAP

Pathogenic

0.95

MetaRNN

Pathogenic

0.99

D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.8

H;.

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.74

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

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over