11-2445279-C-A

Position:

chr11-2445279-C-A

Variant summary

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

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 (★★).

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:3

Conservation

PhyloP100: 0.765

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:

KCNQ1 (HGNC:):

KCNQ1 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNQ1	NM_000218.3 linkuse as main transcript	c.181C>A	p.Pro61Thr	missense_variant	1/16	ENST00000155840.12	NP_000209.2	P51787-1Q96AI9
KCNQ1	NM_001406836.1 linkuse as main transcript	c.181C>A	p.Pro61Thr	missense_variant	1/15		NP_001393765.1
KCNQ1	NM_001406838.1 linkuse as main transcript	c.181C>A	p.Pro61Thr	missense_variant	1/11		NP_001393767.1
KCNQ1	NM_001406837.1 linkuse as main transcript	c.-182C>A		5_prime_UTR_variant	1/17		NP_001393766.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
KCNQ1	ENST00000155840.12 linkuse as main transcript	c.181C>A	p.Pro61Thr	missense_variant	1/16	1	NM_000218.3	ENSP00000155840.2	P51787-1
KCNQ1	ENST00000646564.2 linkuse as main transcript	c.181C>A	p.Pro61Thr	missense_variant	1/11			ENSP00000495806.2	A0A2R8YEQ9
KCNQ1	ENST00000496887.7 linkuse as main transcript	c.24-104C>A		intron_variant		5		ENSP00000434560.2	E9PPZ0
KCNQ1	ENST00000345015.4 linkuse as main transcript	n.-43C>A		upstream_gene_variant		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

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000963

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:

0.0000166

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000267

AC:

AN:

149850

Hom.:

Cov.:

AF XY:

0.0000410

AC XY:

AN XY:

73116

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000266

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:

0.0000340

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Nov 15, 2017

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

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Aug 16, 2019

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. -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 22, 2023

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

BayesDel_addAF

Uncertain

0.050

BayesDel_noAF

Benign

-0.17

CADD

Benign

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

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

Varity_R

0.051

gMVP

0.32

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

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