11-2445117-C-T

Position:

chr11-2445117-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM1BP4

The ENST00000155840.12(KCNQ1):c.19C>T(p.Pro7Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000332 in 1,100,404 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). Synonymous variant affecting the same amino acid position (i.e. P7P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00018 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00036 ( 0 hom. )

Consequence

KCNQ1
ENST00000155840.12 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7B:1O:1

Conservation

PhyloP100: 0.235

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 1 ACMG points.

PM1

In a region_of_interest Disordered (size 27) in uniprot entity KCNQ1_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in ENST00000155840.12

BP4

Computational evidence support a benign effect (MetaRNN=0.3163181).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
KCNQ1	NM_000218.3 linkuse as main transcript	c.19C>T	p.Pro7Ser	missense_variant	1/16	ENST00000155840.12	NP_000209.2
KCNQ1	NM_001406836.1 linkuse as main transcript	c.19C>T	p.Pro7Ser	missense_variant	1/15		NP_001393765.1
KCNQ1	NM_001406838.1 linkuse as main transcript	c.19C>T	p.Pro7Ser	missense_variant	1/11		NP_001393767.1
KCNQ1	NM_001406837.1 linkuse as main transcript	c.-344C>T		5_prime_UTR_variant	1/17		NP_001393766.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNQ1	ENST00000155840.12 linkuse as main transcript	c.19C>T	p.Pro7Ser	missense_variant	1/16	1	NM_000218.3	ENSP00000155840	P1	P51787-1
KCNQ1	ENST00000646564.2 linkuse as main transcript	c.19C>T	p.Pro7Ser	missense_variant	1/11			ENSP00000495806
KCNQ1	ENST00000496887.7 linkuse as main transcript	c.24-266C>T		intron_variant		5		ENSP00000434560

Frequencies

GnomAD3 genomes

AF:

0.000182

AC:

AN:

148034

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:

0.000392

Gnomad OTH

AF:

0.000489

GnomAD4 exome

AF:

0.000356

AC:

339

AN:

952262

Hom.:

Cov.:

AF XY:

0.000360

AC XY:

162

AN XY:

449890

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:

0.000383

Gnomad4 OTH exome

AF:

0.000560

GnomAD4 genome

AF:

0.000176

AC:

AN:

148142

Hom.:

Cov.:

AF XY:

0.000125

AC XY:

AN XY:

72198

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:

0.000377

Gnomad4 OTH

AF:

0.000484

Alfa

AF:

0.000214

Hom.:

Bravo

AF:

0.000136

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:7Benign:1Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 07, 2024	Variant summary: KCNQ1 c.19C>T (p.Pro7Ser) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The frequency data for this variant in gnomAD is considered unreliable, as metrics indicate poor data quality at this position. c.19C>T has been reported in the literature in heterozygous individuals affected with autosomal dominant Long QT syndrome 1 (Johnson_2008, Thompson_2018, Yoneda_2021). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 18452873, 29790872, 34495297). ClinVar contains an entry for this variant (Variation ID: 53028). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -
Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Oct 13, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Variant not reported in ExAC but has been reported in 1 affected individual (LQTS). In ClinVar without clinical assertion - 2 submitters (no stars). -

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	AiLife Diagnostics, AiLife Diagnostics	Aug 25, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	KCNQ1: PS4:Moderate, PM2:Supporting, PP2, PP3 -

Long QT syndrome 1

Uncertain:1

Uncertain significance, criteria provided, single submitter

research

HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology

Sep 02, 2021

- -

Beckwith-Wiedemann syndrome;C1837014: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

Fulgent Genetics, Fulgent Genetics

Nov 09, 2021

- -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 16, 2021

The c.19C>T (p.P7S) alteration is located in exon 1 (coding exon 1) of the KCNQ1 gene. This alteration results from a C to T substitution at nucleotide position 19, causing the proline (P) at amino acid position 7 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Long QT syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 02, 2023

- -

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:18452873;PMID:19716085;PMID:19862833). 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

0.067

BayesDel_addAF

Pathogenic

0.17

BayesDel_noAF

Uncertain

0.0

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.40

Eigen

Benign

-0.54

Eigen_PC

Benign

-0.49

FATHMM_MKL

Benign

0.052

LIST_S2

Benign

0.57

M_CAP

Pathogenic

0.99

MetaRNN

Benign

0.32

MetaSVM

Uncertain

0.69

MutationAssessor

Benign

1.4

MutationTaster

Benign

0.98

PrimateAI

Pathogenic

0.85

PROVEAN

Benign

-0.76

REVEL

Uncertain

0.50

Sift

Uncertain

0.014

Sift4G

Pathogenic

0.0

Polyphen

0.047

Vest4

0.16

MutPred

0.70

Gain of phosphorylation at P7 (P = 0.0022);

MVP

0.91

MPC

1.2

ClinPred

0.13

GERP RS

2.7

Varity_R

0.069

gMVP

0.47

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