rs199472683

Positions:

chr11-2445483-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM1

The NM_000218.3(KCNQ1):c.385G>A(p.Val129Ile) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.0000069 in 1,594,412 control chromosomes in the GnomAD database, with no homozygous occurrence. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000035 ( 0 hom. )

Consequence

KCNQ1
NM_000218.3 missense, splice_region

Scores

Splicing: ADA: 0.5535

Clinical Significance

Uncertain significance criteria provided, single submitter U:1O:1

Conservation

PhyloP100: 5.73

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 2 ACMG points.

PM1

In a transmembrane_region Helical; Name=Segment S1 (size 20) in uniprot entity KCNQ1_HUMAN there are 12 pathogenic changes around while only 1 benign (92%) in NM_000218.3

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
KCNQ1	NM_000218.3 linkuse as main transcript	c.385G>A	p.Val129Ile	missense_variant, splice_region_variant	1/16	ENST00000155840.12	NP_000209.2
KCNQ1	NM_001406836.1 linkuse as main transcript	c.385G>A	p.Val129Ile	missense_variant, splice_region_variant	1/15		NP_001393765.1
KCNQ1	NM_001406837.1 linkuse as main transcript	c.23G>A	p.Arg8His	missense_variant, splice_region_variant	1/17		NP_001393766.1
KCNQ1	NM_001406838.1 linkuse as main transcript	c.385G>A	p.Val129Ile	missense_variant, splice_region_variant	1/11		NP_001393767.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNQ1	ENST00000155840.12 linkuse as main transcript	c.385G>A	p.Val129Ile	missense_variant, splice_region_variant	1/16	1	NM_000218.3	ENSP00000155840	P1	P51787-1
KCNQ1	ENST00000345015.4 linkuse as main transcript	n.162G>A		splice_region_variant, non_coding_transcript_exon_variant	1/3	1
KCNQ1	ENST00000496887.7 linkuse as main transcript	c.124G>A	p.Val42Ile	missense_variant, splice_region_variant	2/16	5		ENSP00000434560
KCNQ1	ENST00000646564.2 linkuse as main transcript	c.385G>A	p.Val129Ile	missense_variant, splice_region_variant	1/11			ENSP00000495806

Frequencies

GnomAD3 genomes

AF:

0.0000394

AC:

AN:

152226

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000145

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000187

AC:

AN:

214296

Hom.:

AF XY:

0.0000251

AC XY:

AN XY:

119372

show subpopulations

Gnomad AFR exome

AF:

0.000155

Gnomad AMR exome

AF:

0.0000300

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:

0.0000104

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000347

AC:

AN:

1442186

Hom.:

Cov.:

AF XY:

0.00000418

AC XY:

AN XY:

717520

show subpopulations

Gnomad4 AFR exome

AF:

0.0000598

Gnomad4 AMR exome

AF:

0.0000226

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000117

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.00e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000394

AC:

AN:

152226

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74366

show subpopulations

Gnomad4 AFR

AF:

0.000145

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:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000529

ExAC

AF:

0.00000854

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1Other:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Long QT syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 07, 2023

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.Val129 amino acid residue in KCNQ1. Other variant(s) that disrupt this residue have been observed in individuals with KCNQ1-related conditions (PMID: 27920829; Invitae), which suggests that this may be a clinically significant amino acid residue. Experimental studies have shown that this missense change does not substantially affect KCNQ1 function (PMID: 29532034, 30571187). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant¬†is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 67068). This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 129 of the KCNQ1 protein (p.Val129Ile). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with KCNQ1-related conditions. -

not provided

Other:1

not provided, no classification provided

literature only

Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust

This variant has been reported in the following publications (PMID:14661677;PMID:19841300). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.44

BayesDel_addAF

Pathogenic

0.21

BayesDel_noAF

Uncertain

0.060

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.71

.;D;.

Eigen

Uncertain

0.35

Eigen_PC

Uncertain

0.34

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.86

D;D;D

M_CAP

Uncertain

0.18

MetaRNN

Uncertain

0.50

T;T;T

MetaSVM

Uncertain

0.73

MutationAssessor

Benign

2.0

.;M;.

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.65

PROVEAN

Benign

-0.71

N;N;.

REVEL

Uncertain

0.60

Sift

Benign

0.078

T;T;.

Sift4G

Benign

0.12

T;T;.

Polyphen

0.88

.;P;.

Vest4

0.33

MutPred

0.63

.;Loss of catalytic residue at V129 (P = 0.021);.;

MVP

0.94

MPC

1.3

ClinPred

0.36

GERP RS

3.2

Varity_R

0.27

gMVP

0.83

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.55

dbscSNV1_RF

Benign

0.54

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