NM_000218.3:c.1861G>A

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 1P and 2B. PP2BP4_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. 14/23 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

Publications

8 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 links:

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

KCNQ1-AS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -1 ACMG points.

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.

BP4

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNQ1	NM_000218.3 link	c.1861G>A	p.Gly621Ser	missense_variant	Exon 16 of 16	ENST00000155840.12	NP_000209.2	P51787-1Q96AI9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNQ1	ENST00000155840.12 link	c.1861G>A	p.Gly621Ser	missense_variant	Exon 16 of 16	1	NM_000218.3	ENSP00000155840.2		P51787-1

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

GnomAD2 exomes

AF:

0.0000508

AC:

AN:

177000

AF XY:

0.0000421

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 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

African (AFR)

AF:

0.000308

AC:

AN:

32484

American (AMR)

AF:

0.000129

AC:

AN:

38766

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25340

East Asian (EAS)

AF:

0.0000538

AC:

AN:

37196

South Asian (SAS)

AF:

0.0000124

AC:

AN:

80622

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49262

Middle Eastern (MID)

AF:

0.000175

AC:

AN:

5716

European-Non Finnish (NFE)

AF:

0.0000285

AC:

AN:

1088534

Other (OTH)

AF:

0.0000853

AC:

AN:

58640

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000230

AC:

AN:

152314

Hom.:

Cov.:

AF XY:

0.000188

AC XY:

AN XY:

74486

show subpopulations

African (AFR)

AF:

0.000457

AC:

AN:

41560

American (AMR)

AF:

0.000915

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

68018

Other (OTH)

AF:

0.00

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000158

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

Dec 02, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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 5.6e-05 in 177610 control chromosomes, including 1 homozygote. This frequency is not significantly higher than estimated for a pathogenic variant in KCNQ1 causing Jervell And Lange-Nielsen Syndrome (5.6e-05 vs 0.0024), allowing no conclusion about variant significance. c.1861G>A has been reported in the literature in the presumed heterozygous state in multiple 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, Martinez-Barrios_2023), but it was also reported in an apparently healthy control (Ackerman_2003) and no segregation with disease was observed in families. These reports do not provide unequivocal conclusions about association of the variant with KCNQ1-related conditions. 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: 14661677, 32268277, 25447171, 29247119, 32917565, 36693943). ClinVar contains an entry for this variant (Variation ID: 67061). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Mar 22, 2017

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Aug 06, 2024

All of Us Research Program, National Institutes of Health

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Dec 07, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

Sep 01, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Cardiovascular phenotype

Uncertain:1

Jan 21, 2021

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Feb 15, 2024

Color Diagnostics, LLC DBA Color Health

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not provided

Other:1

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

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

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

CardioboostArm

Benign

0.00015

BayesDel_addAF

Benign

-0.13

BayesDel_noAF

Uncertain

-0.070

CADD

Benign

6.8

(source)

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;.;.

PhyloP100

0.025

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

Mutation Taster

=41/59

disease causing

(source)

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

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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