11-2847833-G-A

Position:

chr11-2847833-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM1BP4_Moderate

The NM_000218.3(KCNQ1):c.1861G>A(p.Gly621Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000574 in 1,568,874 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict 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. G621D) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00023 ( 1 hom., cov: 33)

Exomes 𝑓: 0.000039 ( 0 hom. )

Consequence

KCNQ1
NM_000218.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6B:1O:1

Conservation

PhyloP100: 0.0250

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-AS1 (HGNC:42790): (KCNQ1 antisense RNA 1)

KCNQ1-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM1

In a coiled_coil_region (size 36) in uniprot entity KCNQ1_HUMAN there are 45 pathogenic changes around while only 2 benign (96%) in NM_000218.3

BP4

Computational evidence support a benign effect (MetaRNN=0.17476952).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNQ1	NM_000218.3 linkuse as main transcript	c.1861G>A	p.Gly621Ser	missense_variant	16/16	ENST00000155840.12
KCNQ1-AS1	NR_130721.1 linkuse as main transcript	n.778-7391C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNQ1	ENST00000155840.12 linkuse as main transcript	c.1861G>A	p.Gly621Ser	missense_variant	16/16	1	NM_000218.3	P1	P51787-1
KCNQ1-AS1	ENST00000440887.2 linkuse as main transcript	n.777-7391C>T		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes

AF:

0.000230

AC:

AN:

152196

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000459

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000916

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000508

AC:

AN:

177000

Hom.:

AF XY:

0.0000421

AC XY:

AN XY:

94988

show subpopulations

Gnomad AFR exome

AF:

0.000192

Gnomad AMR exome

AF:

0.000109

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000149

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000140

Gnomad OTH exome

AF:

0.000209

GnomAD4 exome

AF:

0.0000388

AC:

AN:

1416560

Hom.:

Cov.:

AF XY:

0.0000400

AC XY:

AN XY:

700550

show subpopulations

Gnomad4 AFR exome

AF:

0.000308

Gnomad4 AMR exome

AF:

0.000129

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000538

Gnomad4 SAS exome

AF:

0.0000124

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000285

Gnomad4 OTH exome

AF:

0.0000853

GnomAD4 genome

AF:

0.000230

AC:

AN:

152314

Hom.:

Cov.:

AF XY:

0.000188

AC XY:

AN XY:

74486

show subpopulations

Gnomad4 AFR

AF:

0.000457

Gnomad4 AMR

AF:

0.000915

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000637

Hom.:

Bravo

AF:

0.000302

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ExAC

AF:

0.0000420

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:6Benign: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	Nov 23, 2021	Variant summary: KCNQ1 c.1861G>A (p.Gly621Ser) 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 0.00024 in 151578 control chromosomes in the gnomAD v3.1.2 database, including 1 homozygote. The observed variant frequency is approximately 2-fold of the estimated maximal expected allele frequency for a pathogenic variant in KCNQ1 causing Arrhythmia phenotype (0.0001), strongly suggesting that the variant is benign. c.1861G>A has been reported in the literature in individuals affected by sudden unexplained death and also in an individual affected with Long QT Syndrome (Campuzano_2014, Lin_2017, Campuzano_2020, Ripoll-Vera_2021), but it was also reported in an apparently healthy control (Ackerman_2003). These reports do not provide unequivocal conclusions about association of the variant with Arrhythmia. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly benign. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Mar 22, 2017	The G621S variant in the KCNQ1 gene has been published in an 11-month-old male with sudden cardiac death during sleeping. However, this individual harbored several cardiogenetic variants, including a TTN variant predicted to be disease-causing (Campuzano et al.,2014). The G621S variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. However, this substitution occurs at a position that is not conserved across species, and in silico analysis predicts this variant likely does not alter the protein structure/function. Finally, although G621S is not observed at a significant frequency in large population cohorts, it has been reported as a rare control variant in at least one ostensibly healthy Black individual (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server; Ackerman et al., 2003; Kapa et al., 2009; Giudicessi et al., 2012). -

Long QT syndrome

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Feb 05, 2024	This missense variant replaces glycine with serine at codon 621 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). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in two individuals affected with sudden cardiac death (PMID: 25447171, 32917565) and in an individual affected with long QT syndrome (PMID: 32268277). This variant has also been identified in 16/208352 chromosomes in the general population, including 1 homozygous individual in Latino, 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. -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Nov 14, 2023	- -

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

Sep 01, 2021

- -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 21, 2021

The c.1861G>A (p.G621S) alteration is located in exon 16 (coding exon 16) of the KCNQ1 gene. This alteration results from a G to A substitution at nucleotide position 1861, causing the glycine (G) at amino acid position 621 to be replaced by a serine (S). 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

Feb 09, 2023

This missense variant replaces glycine with serine at codon 621 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). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in two individuals affected with sudden cardiac death (PMID: 25447171, 32917565) and in an individual affected with long QT syndrome (PMID: 32268277). This variant has also been identified in 16/208352 chromosomes in the general population, including 1 homozygous individual in Latino, 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. -

not provided

Other:1

not provided, no classification provided

literature only

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

This variant has been reported in the following publications (PMID:14661677;PMID:19841300). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.076

BayesDel_addAF

Benign

-0.13

BayesDel_noAF

Uncertain

-0.070

CADD

Benign

6.8

DANN

Benign

0.83

DEOGEN2

Benign

0.26

T;.;.

Eigen

Benign

-1.8

Eigen_PC

Benign

-1.8

FATHMM_MKL

Benign

0.029

LIST_S2

Benign

0.60

T;T;T

M_CAP

Pathogenic

0.76

MetaRNN

Benign

0.17

T;T;T

MetaSVM

Pathogenic

1.2

MutationAssessor

Benign

-0.34

N;.;.

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.38

PROVEAN

Benign

0.51

N;N;.

REVEL

Uncertain

0.57

Sift

Benign

0.46

T;T;.

Sift4G

Benign

0.74

T;T;.

Polyphen

0.0050

B;.;.

Vest4

0.073

MVP

0.68

MPC

0.37

ClinPred

0.0047

GERP RS

-3.4

Varity_R

0.10

gMVP

0.59

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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