rs1273257287

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM1PP2

The NM_000218.3(KCNQ1):c.181C>A(p.Pro61Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000161 in 1,303,178 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 Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P61S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000027 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000015 ( 0 hom. )

Consequence

KCNQ1
NM_000218.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4

Conservation

PhyloP100: 0.765

Publications

0 publications found

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 Gene-Disease associations (from GenCC):

long QT syndrome
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
long QT syndrome 1
Inheritance: AD, AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
Jervell and Lange-Nielsen syndrome
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
Jervell and Lange-Nielsen syndrome 1
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), G2P
atrial fibrillation, familial, 3
Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
short QT syndrome
Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: ClinGen, Orphanet
short QT syndrome type 2
Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
familial atrial fibrillation
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Jervell and Lange-Nielsen syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
hypertrophic cardiomyopathy
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

KCNQ1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM1

In a topological_domain Cytoplasmic (size 120) in uniprot entity KCNQ1_HUMAN there are 14 pathogenic changes around while only 1 benign (93%) in NM_000218.3

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 212 curated pathogenic missense variants (we use a threshold of 10). The gene has 12 curated benign missense variants. Gene score misZ: 1.8321 (below the threshold of 3.09). Trascript score misZ: 0.90233 (below the threshold of 3.09). GenCC associations: The gene is linked to short QT syndrome type 2, long QT syndrome 1, Jervell and Lange-Nielsen syndrome 1, long QT syndrome, short QT syndrome, Jervell and Lange-Nielsen syndrome, hypertrophic cardiomyopathy, familial atrial fibrillation, atrial fibrillation, familial, 3.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNQ1	NM_000218.3 link	c.181C>A	p.Pro61Thr	missense_variant	Exon 1 of 16	ENST00000155840.12	NP_000209.2	P51787-1Q96AI9
KCNQ1	NM_001406836.1 link	c.181C>A	p.Pro61Thr	missense_variant	Exon 1 of 15		NP_001393765.1
KCNQ1	NM_001406838.1 link	c.181C>A	p.Pro61Thr	missense_variant	Exon 1 of 11		NP_001393767.1
KCNQ1	NM_001406837.1 link	c.-182C>A		5_prime_UTR_variant	Exon 1 of 17		NP_001393766.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNQ1	ENST00000155840.12 link	c.181C>A	p.Pro61Thr	missense_variant	Exon 1 of 16	1	NM_000218.3	ENSP00000155840.2		P51787-1

Frequencies

GnomAD3 genomes

AF:

0.0000267

AC:

AN:

149850

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000266

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

GnomAD4 exome

AF:

0.0000147

AC:

AN:

1153328

Hom.:

Cov.:

AF XY:

0.0000161

AC XY:

AN XY:

559752

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

23172

American (AMR)

AF:

0.0000963

AC:

AN:

10382

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

15052

East Asian (EAS)

AF:

0.00

AC:

AN:

25846

South Asian (SAS)

AF:

0.00

AC:

AN:

40414

European-Finnish (FIN)

AF:

0.00

AC:

AN:

24492

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3224

European-Non Finnish (NFE)

AF:

0.0000166

AC:

AN:

964554

Other (OTH)

AF:

0.00

AC:

AN:

46192

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.513

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000267

AC:

AN:

149850

Hom.:

Cov.:

AF XY:

0.0000410

AC XY:

AN XY:

73116

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41042

American (AMR)

AF:

0.000266

AC:

AN:

15046

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3450

East Asian (EAS)

AF:

0.00

AC:

AN:

5144

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9684

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67374

Other (OTH)

AF:

0.00

AC:

AN:

2054

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000340

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Nov 15, 2017

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.Pro61Thr variant in KCNQ1 has not been previously reported in individuals with hearing loss or long QT syndrome and was absent from large population studi es. Computational prediction tools and conservation analysis suggest that the p. Pro61Thr variant may not impact the protein, though this information is not pred ictive enough to rule out pathogenicity. In summary, the clinical significance o f the p.Pro61Thr variant is uncertain. ACMG/AMP Criteria applied: PM2, BP4. -

not provided

Uncertain:1

Aug 16, 2019

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Has not been previously published as pathogenic or benign to our knowledge; Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes splice predictors and evolutionary conservation, suggests this variant may impact gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown. -

Long QT syndrome

Uncertain:1

Sep 22, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces proline, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 61 of the KCNQ1 protein (p.Pro61Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of KCNQ1-related conditions (PMID: 34505893). ClinVar contains an entry for this variant (Variation ID: 517627). 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. 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

Nov 22, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.P61T variant (also known as c.181C>A), located in coding exon 1 of the KCNQ1 gene, results from a C to A substitution at nucleotide position 181. The proline at codon 61 is replaced by threonine, an amino acid with highly similar properties. This alteration has been reported in association with long QT syndrome (Walsh R et al. Genet Med, 2021 Jan;23:47-58; Schwartz PJ et al. Eur Heart J, 2021 Dec;42:4743-4755). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.073

CardioboostArm

Benign

0.014

BayesDel_addAF

Uncertain

0.050

BayesDel_noAF

Benign

-0.17

CADD

Benign

(source)

DANN

Benign

0.86

DEOGEN2

Benign

0.41

Eigen

Benign

-0.80

Eigen_PC

Benign

-0.86

FATHMM_MKL

Benign

0.083

LIST_S2

Benign

0.37

M_CAP

Pathogenic

0.95

MetaRNN

Benign

0.25

MetaSVM

Uncertain

0.69

MutationAssessor

Benign

1.1

PhyloP100

0.77

PrimateAI

Pathogenic

0.83

PROVEAN

Benign

-0.98

REVEL

Uncertain

0.33

Sift

Benign

0.088

Sift4G

Benign

0.68

Polyphen

0.089

Vest4

0.15

MutPred

0.25

Gain of phosphorylation at P61 (P = 0.0088);

MVP

0.92

MPC

1.3

ClinPred

0.091

GERP RS

1.9

PromoterAI

-0.014

Neutral

(source)

Varity_R

0.051

gMVP

0.32

Mutation Taster

=76/24

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.29

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.29

Position offset: -3

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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rs1273257287

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over