rs750409379

Positions:

chr11-2777026-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM1BP4BP6

The ENST00000155840.12(KCNQ1):c.1726G>A(p.Val576Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000694 in 1,613,946 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). Synonymous variant affecting the same amino acid position (i.e. V576V) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000075 ( 0 hom. )

Consequence

KCNQ1
ENST00000155840.12 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:3

Conservation

PhyloP100: 0.617

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 Uncertain_significance. Variant got 0 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 12 uncertain in ENST00000155840.12

BP4

Computational evidence support a benign effect (MetaRNN=0.3283702).

BP6

Variant 11-2777026-G-A is Benign according to our data. Variant chr11-2777026-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 200813.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Uncertain_significance=4, Likely_benign=2}. Variant chr11-2777026-G-A is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNQ1	NM_000218.3 linkuse as main transcript	c.1726G>A	p.Val576Ile	missense_variant	14/16	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.1726G>A	p.Val576Ile	missense_variant	14/16	1	NM_000218.3	ENSP00000155840	P1	P51787-1
KCNQ1	ENST00000335475.6 linkuse as main transcript	c.1345G>A	p.Val449Ile	missense_variant	14/16	1		ENSP00000334497		P51787-2
KCNQ1	ENST00000496887.7 linkuse as main transcript	c.1369G>A	p.Val457Ile	missense_variant	14/16	5		ENSP00000434560
KCNQ1	ENST00000646564.2 linkuse as main transcript	c.1186G>A	p.Val396Ile	missense_variant	9/11			ENSP00000495806

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152134

Hom.:

Cov.:

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:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000637

AC:

AN:

250990

Hom.:

AF XY:

0.0000810

AC XY:

AN XY:

135778

show subpopulations

Gnomad AFR exome

AF:

0.0000617

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000131

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000882

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000746

AC:

109

AN:

1461812

Hom.:

Cov.:

AF XY:

0.0000866

AC XY:

AN XY:

727204

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.000139

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000782

Gnomad4 OTH exome

AF:

0.0000994

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152134

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74314

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:

0.0000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000653

Hom.:

Bravo

AF:

0.0000302

ExAC

AF:

0.0000741

AC:

EpiCase

AF:

0.000164

EpiControl

AF:

0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Atrial fibrillation, familial, 3;C1865019:Short QT syndrome type 2;C4551509:Jervell and Lange-Nielsen syndrome 1;C4551647:Long QT syndrome 1

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

New York Genome Center

Apr 06, 2022

The c.1726G>A p.(Val576Ile) variant in KCNQ1 has previously been reported heterozygous in an individual with long QT syndrome [PMID: 23174487] and compound heterozygous in an individual with Jervell and Lange-Nielsen syndrome without deafness [PMID: 23392653]. This variant has been deposited in ClinVar [ClinVar ID:200813] as Variant of Uncertain Significance, Likely benign, and Benign. The 1726G>A variant is observed in 24 alleles (~0.003% MAF with 0 homozygotes) in population databases (gnomAD v2.1.1 and v3.1.2, TOPMed Freeze 8), suggesting it is not a common benign variant in the populations represented in those databases.The c.1726G>A variant is located in exon 14 of this 16-exon gene and predicted to replace a poorly conserved valine amino acid with isoleucine at position 576. In silico predictions are inconclusive of the variant's effect (CADD v1.6 = 17.03, REVEL = 0.622); however, there are no functional studies to support or refute these predictions. Based on available evidence this c.1726G>A p.(Val576Ile) variant identified in KCNQ1 is classified as a Variant of Uncertain Significance. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Mar 08, 2024

In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 23392653, 23174487, 32048431) -

Long QT syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 11, 2023

This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 576 of the KCNQ1 protein (p.Val576Ile). This variant is present in population databases (rs750409379, gnomAD 0.01%). This missense change has been observed in individual(s) with clinical features of KCNQ1-related conditions (PMID: 18752142, 23174487, 23392653). ClinVar contains an entry for this variant (Variation ID: 200813). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The isoleucine 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. -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 12, 2023

The p.V576I variant (also known as c.1726G>A), located in coding exon 14 of the KCNQ1 gene, results from a G to A substitution at nucleotide position 1726. The valine at codon 576 is replaced by isoleucine, an amino acid with highly similar properties, and is located in the C-terminal, cytoplasmic region of the protein. This variant co-occurred with a second KCNQ1 variant in an individual with long QT syndrome and intact hearing whose mother, with a normal QTc interval, carried only the p.V576I variant; however, the father was unavailable for testing (Giudicessi JR et al. Circ Cardiovasc Genet, 2013 Apr;6:193-200). This variant has also been detected in long QT syndrome cohorts; however, details were limited (Mullally J et al. Heart Rhythm, 2013 Mar;10:378-82; Berge KE et al. Scand. J. Clin. Lab. Invest. 2008 ;68(5):362-8). This amino acid position is not well 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. -

Long QT syndrome 1

Benign:1

Benign, criteria provided, single submitter

clinical testing

Mendelics

May 28, 2019

- -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Aug 13, 2015

p.Val576Ile in exon 14 of KCNQ1: This variant is not expected to have clinical s ignificance due to a lack of conservation across species, including mammals. Of note, 13 mammals have an Ile at this position despite high nearby amino acid con servation. In addition, computational prediction tools do not suggest a high lik elihood of impact to the protein. It has also been identified in 5/65838 Europea n chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstit ute.org). Although this variant has been reported in 2 individuals with LQTS (1 with intact hearing who carried a second likely pathogenic variant) (Mullally 20 13, Giudicessi 2013), based on the lack of conservation at this position, this v ariant is likely benign. -

Cardiac arrhythmia

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Nov 06, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.072

BayesDel_addAF

Uncertain

0.10

BayesDel_noAF

Pathogenic

0.15

CADD

Benign

DANN

Benign

0.71

DEOGEN2

Uncertain

0.68

D;.;.

Eigen

Benign

-0.77

Eigen_PC

Benign

-0.72

FATHMM_MKL

Benign

0.40

LIST_S2

Benign

0.60

T;T;T

M_CAP

Pathogenic

0.78

MetaRNN

Benign

0.33

T;T;T

MetaSVM

Uncertain

0.74

MutationAssessor

Benign

0.60

N;.;.

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.41

PROVEAN

Benign

-0.37

N;.;N

REVEL

Uncertain

0.62

Sift

Benign

0.34

T;.;T

Sift4G

Benign

0.30

T;.;T

Polyphen

0.0030

B;.;B

Vest4

0.23

MVP

0.87

MPC

0.31

ClinPred

0.020

GERP RS

1.7

Varity_R

0.026

gMVP

0.87

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.

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