11-2572885-A-G

Variant names:

• chr11-2572885-A-G
• rs199472728
• NM_000218.3:c.820A>G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM1

The NM_000218.3(KCNQ1):​c.820A>G​(p.Ile274Val) variant causes a missense change. The variant allele was found at a frequency of 0.000199 in 1,613,666 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00021 (0 hom.)
• Consequence: KCNQ1 NM_000218.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:8 B:3 O:1
• Conservation: PhyloP100: 6.90

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM1: In a helix (size 25) in uniprot entity KCNQ1_HUMAN there are 38 pathogenic changes around while only 0 benign (100%) in NM_000218.3

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNQ1	NM_000218.3	c.820A>G	p.Ile274Val	missense_variant	Exon 6 of 16	ENST00000155840.12	NP_000209.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNQ1	ENST00000155840.12	c.820A>G	p.Ile274Val	missense_variant	Exon 6 of 16	1	NM_000218.3	ENSP00000155840.2
KCNQ1	ENST00000335475.6	c.439A>G	p.Ile147Val	missense_variant	Exon 6 of 16	1		ENSP00000334497.5
KCNQ1	ENST00000496887.7	c.559A>G	p.Ile187Val	missense_variant	Exon 7 of 16	5		ENSP00000434560.2
KCNQ1	ENST00000646564.2	c.478-10550A>G		intron_variant	Intron 2 of 10			ENSP00000495806.2

Frequencies

GnomAD3 genomes AF: 0.000125 AC: 19 AN: 152214 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000376

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000180 AC: 45 AN: 250462 Hom.: 1 AF XY: 0.000206 AC XY: 28 AN XY: 135708

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000694

Gnomad NFE exome AF: 0.000257

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.000207 AC: 302 AN: 1461452 Hom.: 0 Cov.: 32 AF XY: 0.000210 AC XY: 153 AN XY: 727044

Gnomad4 AFR exome AF: 0.000119

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000490

Gnomad4 NFE exome AF: 0.000236

Gnomad4 OTH exome AF: 0.000166

GnomAD4 genome AF: 0.000125 AC: 19 AN: 152214 Hom.: 0 Cov.: 33 AF XY: 0.000161 AC XY: 12 AN XY: 74378

Gnomad4 AFR AF: 0.000121

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000376

Gnomad4 NFE AF: 0.000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000136 Hom.: 0

Bravo AF: 0.000110

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000255 AC: 31

EpiCase AF: 0.000109

EpiControl AF: 0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:8 Benign:3 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2

Jul 07, 2022

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies suggest the p.(I274V) variant may alter protein interactions under various experimental conditions; however, it is not known whether these findings are biological or clinically relevant in vivo (Rhodes et al., 2008), and one study showed the alterations were not statistically significant (Huang et al., 2021); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 29197658, 35508187, 33600800, 25637381, 19490272, 19716085, 17999538, 17470695, 17210839, 30420954, 32048431, 31043699, 30615648, 29501667, 18222468, 23465283) -

Oct 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

KCNQ1: PM5 -

Long QT syndrome Uncertain:1 Benign:1

Jan 25, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 05, 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 isoleucine with valine at codon 274 of the KCNQ1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been performed for this variant. Whole-cell patch clamp experiments using transfected CHO cells have suggested that this variant may impact function (PMID: 18222468, 24920132). However, clinical relevance of these observations is not clear. This variant has been reported in individuals affected with sudden infant death syndrome (PMID: 17210839, 18222468) and long QT syndrome (PMID: 17470695). This variant has also been identified in 49/281866 chromosomes in the general population 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. -

SUDDEN INFANT DEATH SYNDROME Pathogenic:1

Jun 01, 2014

CSER _CC_NCGL, University of Washington

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Long QT syndrome 1 Uncertain:1

Dec 12, 2017

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

not specified Uncertain:1

Apr 07, 2020

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant classified as Uncertain Significance - Favor Benign. The p.Ile274Val variant in KCNQ1 has been reported in the heterozygous state in 1 individual with hearing loss where another variant was not identified on the second copy of the KCNQ1 gene, in at least 1 individual with a prolonged QT interval, and 1 individual with sudden infant death syndrome (Moss 2007, Arnestad 2007, Kapplinger 2009, Amin 2012, Goldenberg 2011, LMM data). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID 67109) and has been identified in 0.02% (30/126372) of European chromosomes and 0.06% (16/25754) of Finnish chromosomes, including 1 homozygote, by gnomAD (http://gnomad.broadinstitute.org/). An in vitro patch-clamp study, in which p.Ile274Val was expressed in cultured mammalian cells, suggested that the variant may impact protein function (Rhodes 2008); ; however, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analysis suggest that the p.Ile274Val variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, the clinical significance of the p.Ile274Val variant is uncertain. ACMG/AMP Criteria applied: PP3, PS3_Supporting. -

Atrial fibrillation, familial, 3 Uncertain:1

Dec 12, 2017

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Jervell and Lange-Nielsen syndrome 1 Uncertain:1

Dec 12, 2017

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Cardiac arrhythmia Uncertain:1

Nov 15, 2023

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces isoleucine with valine at codon 274 of the KCNQ1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been performed for this variant. Whole-cell patch clamp experiments using transfected CHO cells have suggested that this variant may impact function (PMID: 18222468, 24920132). However, clinical relevance of these observations is not clear. This variant has been reported in individuals affected with sudden infant death syndrome (PMID: 17210839, 18222468) and long QT syndrome (PMID: 17470695). This variant has also been identified in 49/281866 chromosomes in the general population 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. -

Short QT syndrome type 2 Benign:1

Dec 12, 2017

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -

Cardiovascular phenotype Benign:1

Mar 28, 2020

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Congenital long QT syndrome 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 as associated with Long QT syndrome in the following publications (PMID:17210839;PMID:19716085;PMID:17999538;PMID:17470695). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.45
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.50
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.79	.;D;.
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.95	D;D;D
M_CAP	Pathogenic	0.88	D
MetaRNN	Uncertain	0.49	T;T;T
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	0.93	.;L;.
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-0.98	N;N;N
REVEL	Pathogenic	0.85
Sift	Pathogenic	0.0	D;D;D
Sift4G	Uncertain	0.0030	D;D;T
Polyphen		0.89, 1.0	.;P;D
Vest4		0.93, 0.89
MVP		0.96
MPC		1.1
ClinPred		0.18	T
GERP RS		3.7
Varity_R		0.88
gMVP		0.95

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs199472728; hg19: chr11-2594115; COSMIC: COSV99030386;