rs779383393

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

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

The NM_000218.3(KCNQ1):c.1051T>C(p.Phe351Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,656 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. F351S) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

KCNQ1
NM_000218.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4U:1

Conservation

PhyloP100: 7.49

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 helix (size 19) in uniprot entity KCNQ1_HUMAN there are 35 pathogenic changes around while only 0 benign (100%) in NM_000218.3

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr11-2585231-T-C is described in Lovd as [Pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.942

PP5

Variant 11-2585230-T-C is Pathogenic according to our data. Variant chr11-2585230-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 207968.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=2, Uncertain_significance=1, Pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNQ1	NM_000218.3 link	c.1051T>C	p.Phe351Leu	missense_variant	Exon 8 of 16	ENST00000155840.12	NP_000209.2	P51787-1Q96AI9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
KCNQ1	ENST00000155840.12 link	c.1051T>C	p.Phe351Leu	missense_variant	Exon 8 of 16	1	NM_000218.3	ENSP00000155840.2	P51787-1
KCNQ1	ENST00000335475.6 link	c.670T>C	p.Phe224Leu	missense_variant	Exon 8 of 16	1		ENSP00000334497.5	P51787-2
KCNQ1	ENST00000496887.7 link	c.771+1685T>C		intron_variant	Intron 8 of 15	5		ENSP00000434560.2	E9PPZ0
KCNQ1	ENST00000646564.2 link	c.588+1685T>C		intron_variant	Intron 3 of 10			ENSP00000495806.2	A0A2R8YEQ9

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251344

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135874

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:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461656

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727122

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:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Long QT syndrome 1

Pathogenic:2

Jan 01, 2013

Institute of Medical Genetics and Genomics, Sir Ganga Ram Hospital

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Aug 23, 2023

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Pathogenic:1Uncertain:1

Jan 09, 2020

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 27485560, 27041150) -

Aug 04, 2023

Mayo Clinic Laboratories, Mayo Clinic

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PP3, PM1, PM2, PM3, PS4_moderate -

Long QT syndrome

Pathogenic:1

Dec 19, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 351 of the KCNQ1 protein (p.Phe351Leu). This variant is present in population databases (rs779383393, gnomAD 0.003%). This missense change has been observed in individual(s) with Jervell and Lange-Nielsen syndrome or long QT syndrome (PMID: 27041150, 27485560; internal data). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 207968). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on KCNQ1 protein function. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.32

BayesDel_noAF

Pathogenic

0.31

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.98

D;.

Eigen

Uncertain

0.58

Eigen_PC

Uncertain

0.51

FATHMM_MKL

Uncertain

0.92

LIST_S2

Benign

0.77

T;T

M_CAP

Pathogenic

0.87

MetaRNN

Pathogenic

0.94

D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Uncertain

2.5

M;.

PrimateAI

Pathogenic

0.92

PROVEAN

Pathogenic

-5.7

D;D

REVEL

Pathogenic

0.89

Sift

Benign

0.096

T;T

Sift4G

Pathogenic

0.0

D;T

Polyphen

0.98

D;D

Vest4

0.99

MutPred

0.67

Loss of methylation at K354 (P = 0.0853);.;

MVP

0.97

MPC

1.3

ClinPred

1.0

GERP RS

3.8

Varity_R

0.87

gMVP

0.97

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