rs199472820

Positions:

• chr11-2847833-G-A
• chr11-2847833-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM1 BP4_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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6 B:1 O:1
• Conservation: PhyloP100: 0.0250

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

ACMG classification

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	c.1861G>A	p.Gly621Ser	missense_variant	16/16	ENST00000155840.12
KCNQ1-AS1	NR_130721.1	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	c.1861G>A	p.Gly621Ser	missense_variant	16/16	1	NM_000218.3	P1
KCNQ1-AS1	ENST00000440887.2	n.777-7391C>T		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.000230 AC: 35 AN: 152196 Hom.: 1 Cov.: 33

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: 9 AN: 177000 Hom.: 0 AF XY: 0.0000421 AC XY: 4 AN XY: 94988

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: 55 AN: 1416560 Hom.: 0 Cov.: 31 AF XY: 0.0000400 AC XY: 28 AN XY: 700550

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: 35 AN: 152314 Hom.: 1 Cov.: 33 AF XY: 0.000188 AC XY: 14 AN XY: 74486

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.: 0

Bravo AF: 0.000302

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ExAC AF: 0.0000420 AC: 5

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:6 Benign:1 Other:1

Revision: criteria provided, conflicting classifications

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:1 Benign: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	T
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	N
LIST_S2	Benign	0.60	T;T;T
M_CAP	Pathogenic	0.76	D
MetaRNN	Benign	0.17	T;T;T
MetaSVM	Pathogenic	1.2	D
MutationAssessor	Benign	-0.34	N;.;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.38	T
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	T
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

Other links and lift over

dbSNP: rs199472820; hg19: chr11-2869063; COSMIC: COSV105843728;