rs12720457

Positions:

• chr11-2587620-G-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 4P and 9B. PM1 PM5 BP4_Strong BP6 BS2

The NM_000218.3(KCNQ1):​c.1179G>T​(p.Lys393Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000779 in 1,613,974 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K393M) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00059 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00080 (4 hom.)
• Consequence: KCNQ1 NM_000218.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:21 O:1
• Conservation: PhyloP100: 0.568

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 Likely_benign. Variant got -5 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 12 uncertain in NM_000218.3
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-2587619-A-T is described in Lovd as [Pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.026480198).
• BP6: Variant 11-2587620-G-T is Benign according to our data. Variant chr11-2587620-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 67020.We mark this variant Likely_benign, oryginal submissions are: {not_provided=1, Likely_benign=13, Uncertain_significance=2, Benign=3}. Variant chr11-2587620-G-T is described in Lovd as [Benign]. Variant chr11-2587620-G-T is described in Lovd as [Likely_benign].
• BS2: High Homozygotes in GnomAdExome4 at 4 AD,AR,Digenic gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNQ1	NM_000218.3	c.1179G>T	p.Lys393Asn	missense_variant	9/16	ENST00000155840.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNQ1	ENST00000155840.12	c.1179G>T	p.Lys393Asn	missense_variant	9/16	1	NM_000218.3	P1
KCNQ1	ENST00000335475.6	c.798G>T	p.Lys266Asn	missense_variant	9/16	1
KCNQ1	ENST00000496887.7	c.822G>T	p.Lys274Asn	missense_variant	9/16	5
KCNQ1	ENST00000646564.2	c.639G>T	p.Lys213Asn	missense_variant	4/11

Frequencies

GnomAD3 genomes AF: 0.000591 AC: 90 AN: 152196 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000916

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.000565

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000691

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.00109 AC: 275 AN: 251370 Hom.: 1 AF XY: 0.00126 AC XY: 171 AN XY: 135876

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.00133

Gnomad ASJ exome AF: 0.00248

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00167

Gnomad FIN exome AF: 0.000601

Gnomad NFE exome AF: 0.00112

Gnomad OTH exome AF: 0.00147

GnomAD4 exome AF: 0.000798 AC: 1167 AN: 1461660 Hom.: 4 Cov.: 32 AF XY: 0.000855 AC XY: 622 AN XY: 727146

Gnomad4 AFR exome AF: 0.000657

Gnomad4 AMR exome AF: 0.00148

Gnomad4 ASJ exome AF: 0.00253

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00170

Gnomad4 FIN exome AF: 0.000620

Gnomad4 NFE exome AF: 0.000644

Gnomad4 OTH exome AF: 0.00118

GnomAD4 genome AF: 0.000591 AC: 90 AN: 152314 Hom.: 0 Cov.: 33 AF XY: 0.000671 AC XY: 50 AN XY: 74468

Gnomad4 AFR AF: 0.000144

Gnomad4 AMR AF: 0.000915

Gnomad4 ASJ AF: 0.00202

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00145

Gnomad4 FIN AF: 0.000565

Gnomad4 NFE AF: 0.000691

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000956 Hom.: 0

Bravo AF: 0.000646

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.000814 AC: 7

ExAC AF: 0.00110 AC: 133

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00147

EpiControl AF: 0.00213

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:21 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:7 Other:1

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
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:14678125;PMID:17161064;PMID:17210839;PMID:17470695;PMID:19841300;PMID:19862833). -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 25, 2021	This variant is associated with the following publications: (PMID: 19862833, 25637381, 22949429, 23861362, 31337358, 16556865, 24400285, 23571586, 14661677, 17161064, 14678125, 17210839, 17470695, 19841300, 23396983, 24055113, 25854863, 28074886, 22677073, 30020974, 26970180, 29431662) -
Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 16, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2024	KCNQ1: BS2 -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 14, 2023	- -

Long QT syndrome Uncertain:1 Benign:3

Benign, criteria provided, single submitter	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jun 24, 2013	- -
Likely benign, no assertion criteria provided	research	CSER _CC_NCGL, University of Washington	Jun 01, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -
Uncertain significance, criteria provided, single submitter	research	Dept of Medical Biology, Uskudar University	Jan 08, 2024	Criteria: BS1 -

Long QT syndrome 1 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Jan 01, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	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 determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 16, 2017	Variant summary: The KCNQ1 c.1179G>T (p.Lys393Asn) variant involves the alteration of a non-conserved nucleotide. 3/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in 292/277174 control chromosomes, including 1 homozygous individual, predominantly observed in the Ashkenazi Jewish subpopulation at a frequency of 0.00266 (27/10152). This frequency is about 27 times the estimated maximal expected allele frequency of a pathogenic KCNQ1 variant (0.0001), suggesting this is likely a benign polymorphism found primarily in the populations of Ashkenazi Jewish origin. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as likely benign. Taken together, this variant is classified as likely benign. -
Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jul 20, 2017	p.Lys393Asn in exon 9 of KCNQ1: This variant is not expected to have clinical si gnificance because it has been reported in the literature in both control and cl inical cohorts (Ackerman 2003, Moss 2007, Guidicessi 2012, Crotti 2013). In addi tion, this variant has been identified in 0.3% (27/10152) of Ashkenazi Jewish ch romosomes and 0.2% (52/30782) of South Asian chromosomes including 1 homozygote by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; db SNP rs12720457). Studies have shown that the p.Lys393Asn variant does not impact protein function (Shamgar 2006). Furthermore, the lysine (Lys) at amino acid po sition 393 is not conserved across species, including mammals. Of note, cat has an asparagine (Asn) at this position despite high nearby amino acid conservation . Additional computational analyses do not suggest a high likelihood of impact t o the protein. In summary, this variant is classified as likely benign based on the available data. -

Atrial fibrillation, familial, 3 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

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). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Jervell and Lange-Nielsen syndrome 1 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

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). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Short QT syndrome type 2 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

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). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Cardiomyopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego

Aug 30, 2017

- -

Congenital long QT syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 22, 2018

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. -

Cardiac arrhythmia Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Mar 16, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.42
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Uncertain	0.010
CADD	Benign	22
DANN	Benign	0.96
DEOGEN2	Uncertain	0.76	D;.;.
Eigen	Benign	-0.60
Eigen_PC	Benign	-0.59
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Benign	0.80	T;T;T
M_CAP	Uncertain	0.27	D
MetaRNN	Benign	0.026	T;T;T
MetaSVM	Pathogenic	0.85	D
MutationAssessor	Uncertain	2.2	M;.;.
MutationTaster	Benign	0.98	D;D
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-2.3	N;.;N
REVEL	Uncertain	0.55
Sift	Benign	0.17	T;.;T
Sift4G	Benign	0.19	T;.;T
Polyphen		0.77	P;.;B
Vest4		0.81
MutPred		0.82		Loss of methylation at K393 (P = 0.0144);.;.;
MVP		0.90
MPC		0.44
ClinPred		0.018	T
GERP RS		0.59
Varity_R		0.41
gMVP		0.86

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: rs12720457; hg19: chr11-2608850;