11-2588804-C-T

Position:

chr11-2588804-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_000218.3(KCNQ1):c.1343C>T(p.Pro448Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000397 in 1,613,266 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign 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. P448R) has been classified as Benign.

Frequency

Genomes: 𝑓 0.000059 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000038 ( 0 hom. )

Consequence

KCNQ1
NM_000218.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:9B:3O:1

Conservation

PhyloP100: -0.179

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 Likely_benign. Variant got -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.17283818).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNQ1	NM_000218.3 linkuse as main transcript	c.1343C>T	p.Pro448Leu	missense_variant	10/16	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.1343C>T	p.Pro448Leu	missense_variant	10/16	1	NM_000218.3	ENSP00000155840	P1	P51787-1
KCNQ1	ENST00000335475.6 linkuse as main transcript	c.962C>T	p.Pro321Leu	missense_variant	10/16	1		ENSP00000334497		P51787-2
KCNQ1	ENST00000496887.7 linkuse as main transcript	c.986C>T	p.Pro329Leu	missense_variant	10/16	5		ENSP00000434560
KCNQ1	ENST00000646564.2 linkuse as main transcript	c.803C>T	p.Pro268Leu	missense_variant	5/11			ENSP00000495806

Frequencies

GnomAD3 genomes

AF:

0.0000592

AC:

AN:

152086

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:

0.000132

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000200

AC:

AN:

250376

Hom.:

AF XY:

0.0000221

AC XY:

AN XY:

135480

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:

0.0000265

Gnomad OTH exome

AF:

0.000327

GnomAD4 exome

AF:

0.0000376

AC:

AN:

1461180

Hom.:

Cov.:

AF XY:

0.0000371

AC XY:

AN XY:

726868

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:

0.0000477

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000592

AC:

AN:

152086

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74286

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:

0.000132

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000447

Hom.:

Bravo

AF:

0.0000453

EpiCase

AF:

0.000109

EpiControl

AF:

0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:9Benign:3Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 04, 2020	The p.Pro448Leu variant in KCNQ1 is classified as likely benign due to a lack of conservation across species as 4 mammals carry a leucine (Leu) at this position despite high nearby amino acid conservation. In addition, computational prediction tools predict that this variant does not impact the protein. This variant has been identified in 0.03% (2/7204) of "other population" chromosomes and 0.004% (5/128667) of European chromosomes (http://gnomad.broadinstitute.org). ACMG/AMP Criteria applied: BP4_Strong. -
Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 18, 2024	Variant summary: KCNQ1 c.1343C>T (p.Pro448Leu) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 250376 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1343C>T has been reported in the literature in one affected family member with prolonged QT interval and four unaffected family members, but not in another family members with prolonged QT interval, indicating the variant of interest is not associated with the disease in this family (Kapplinger_2009, Giudicessi_2013). At least one publication reports experimental evidence evaluating an impact on protein function and this variant results in mild effect on protein function (Glazer_2021) in vitro. The following publications have been ascertained in the context of this evaluation (PMID: 23392653, 34930020, 19716085, 25854863, 29033053). ClinVar contains an entry for this variant (Variation ID: 67027). Based on the evidence outlined above, the variant was classified as uncertain significance. -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 05, 2017	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Long QT syndrome

Uncertain:1Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 03, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Nov 28, 2023	This missense variant replaces proline with leucine at codon 448 of the KCNQ1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). A functional study has shown that this variant results in reduced channel peak current density when expressed in Chinese hamster ovary cells (PMID: 34930020). This variant has been reported in a proband affected with long QT syndrome as well as in four relatives with normal QT intervals (PMID: 23392653). In this family, another four individuals with significant QT prolongation were not carriers of this variant, but a different variant in the same gene, p.Pro320Ser (ClinVar variation ID 67130), which was also carried by the proband. This variant has also been reported in another individual noted with syncope in a population screening study, who had no previous indication for cardiac genetic screening (PMID: 34930020). This variant has been identified in 7/281750 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Long QT syndrome 1

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

May 07, 2019

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Atrial fibrillation, familial, 3

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

May 07, 2019

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Jervell and Lange-Nielsen syndrome 1

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

May 07, 2019

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Short QT syndrome type 2

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

May 07, 2019

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Dec 01, 2016

- -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 02, 2019

The c.1343C>T (p.P448L) alteration is located in exon 10 (coding exon 10) of the KCNQ1 gene. This alteration results from a C to T substitution at nucleotide position 1343, causing the proline (P) at amino acid position 448 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Cardiac arrhythmia

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

May 09, 2023

This missense variant replaces proline with leucine at codon 448 of the KCNQ1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). A functional study has shown that this variant results in reduced channel peak current density when expressed in Chinese hamster ovary cells (PMID: 34930020). This variant has been reported in a proband affected with long QT syndrome as well as in four relatives with normal QT intervals (PMID: 23392653). In this family, another four individuals with significant QT prolongation were not carriers of this variant, but a different variant in the same gene, p.Pro320Ser (ClinVar variation ID 67130), which was also carried by the proband. This variant has also been reported in another individual noted with syncope in a population screening study, who had no previous indication for cardiac genetic screening (PMID: 34930020). This variant has been identified in 7/281750 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Congenital long QT syndrome

Other:1

not provided, no classification provided

literature only

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

This variant has been reported as associated with Long QT syndrome in the following publications (PMID:19716085). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.068

BayesDel_addAF

Pathogenic

0.17

BayesDel_noAF

Uncertain

0.070

CADD

Benign

4.9

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.52

D;.;.

Eigen

Benign

-0.86

Eigen_PC

Benign

-0.82

FATHMM_MKL

Benign

0.033

LIST_S2

Benign

0.68

T;T;T

M_CAP

Uncertain

0.28

MetaRNN

Benign

0.17

T;T;T

MetaSVM

Uncertain

0.61

MutationAssessor

Benign

0.34

N;.;.

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.25

PROVEAN

Benign

-1.4

N;.;N

REVEL

Uncertain

0.59

Sift

Benign

0.076

T;.;T

Sift4G

Benign

0.33

T;.;T

Polyphen

0.0

B;.;B

Vest4

0.69

MutPred

0.33

Loss of catalytic residue at P447 (P = 0.0102);.;.;

MVP

0.85

MPC

0.38

ClinPred

0.042

GERP RS

4.1

Varity_R

0.041

gMVP

0.31

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