rs199473410

chr11-2585276-G-Achr11-2585276-G-Cchr11-2585276-G-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM5 PP3_Strong PP5_Very_Strong

The NM_000218.3(KCNQ1):c.1097G>A(p.Arg366Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000616 in 1,461,630 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R366L) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: KCNQ1 NM_000218.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:17 O:1
• Conservation: PhyloP100: 7.50

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 Pathogenic. Variant got 16 ACMG points.

• PM1: In a hotspot region, there are 10 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 12 uncertain in NM_000218.3
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-2585276-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1185948.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.975
• PP5: Variant 11-2585276-G-A is Pathogenic according to our data. Variant chr11-2585276-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 52956.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-2585276-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNQ1	NM_000218.3	c.1097G>A	p.Arg366Gln	missense_variant	8/16	ENST00000155840.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNQ1	ENST00000155840.12	c.1097G>A	p.Arg366Gln	missense_variant	8/16	1	NM_000218.3	P1
KCNQ1	ENST00000335475.6	c.716G>A	p.Arg239Gln	missense_variant	8/16	1
KCNQ1	ENST00000496887.7	c.771+1731G>A		intron_variant		5
KCNQ1	ENST00000646564.2	c.588+1731G>A		intron_variant

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251240 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135834

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: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000616 AC: 9 AN: 1461630 Hom.: 0 Cov.: 31 AF XY: 0.00000688 AC XY: 5 AN XY: 727124

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000540

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:17 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:8

Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Nov 06, 2020	PS3, PS4, PP1_Strong, PM2_Supporting, PM5, PP3, PP4 -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 17, 2022	Reported in multiple individuals with LQTS and observed to segregate with disease (Splawski et al., 2000; Zareba et al., 2003; Kapplinger et al., 2009; Riuro et al., 2014; Yoshinaga et al.,2014; Jimenez-Jaimez et al., 2015; Kapplinger et al., 2015; Itoh et al., 2016; internal GeneDx data); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Functional analysis found that p.(R366Q) resulted in impaired subcellular trafficking of KCNQ1 channels to the plasma membrane (Wilson et al., 2005); This variant is associated with the following publications: (PMID: 32383558, 19934648, 14678125, 24363352, 26669661, 25854863, 24667783, 19716085, 25832545, 28472724, 22581653, 25804018, 29037160, 31737537, 34426522, 34860437, 35588786, 24689698, 15935335, 10973849) -
Pathogenic, no assertion criteria provided	provider interpretation	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Apr 21, 2017	GENETIC TEST RESULTS Our patient has a clinical phenotype of LQTS, with QTc interval of >500 msec on some EKGs. She had genetic testing for LQTS with the Invitae laboratory. The following 17 genes were evaluated for sequence changes and exonic deletions/duplications: AKAP9, ANK2, CACNA1C, CALM1, CALM2, CALM3, CAV3, KCNE1, KCNE2, KCNH2, KCNJ2, KCNJ5, KCNQ1, SCN4B, SCN5A, SNTA1, TRDN. Results showed two variants: • p.Arg366Gln (R366Q; c.1097G>A) in the KCNQ1 gene (diagnostic of LQTS type 1) • p.Ile688Asn (I688N; c.2063T>A) in the ANK2 gene p.Arg366Gln (R366Q; c.1097G>A) in exon 8 of the KCNQ1 gene (NM_000218.2) Chromosome location: 11:2606506 G / A Invitae classifies Arg366Gln as Pathogenic. Based on the information reviewed below, including multiple reports in well-phenotyped patients in the literature, strong segregation data, and a near absence from population datasets, we classify it as Very Likely Disease Causing, concluding that there is sufficient evidence for its pathogenicity to warrant using it for diagnosis of long QT syndrome type 1 (LQT1) and predictive genetic testing. This variant has previously been reported multiple times, in approximately 7 unrelated families with LQTS. Other variants at this same amino acid have also been reported multiple times in LQTS patients. Zareba et al. (2003; PMID 14678125) reported it in 2 individuals with LQT1 from the International LQTS Registry (it is possible that they are related). They also reported a different amino acid change, Arg366Trp, at this same codon in one patient. Crotti et al. reported it in 2 individuals with LQTS from 2 families (2012; PMID 23158531); these cases may overlap with the Zareba cases. Itoh et al. (2016; PMID 26669661) reported it in 3 separate LQTS families, and also reported Arg366Trp in 5 families and Arg366Pro in one family. Ertugrul et al. (2014; PMID 25804018) reported it in a LQTS patient who also had a variant in SCN5A. Strong segregation data is available: Tekin et al. reported it in homozygous form in a deaf Turkish brother and sister each with Jervell and Lange-Nielsen syndrome (2014; PMID 24689698), and confirmed that both of their hearing parents were heterozygous. One of the other missense substitutions at this codon (p.Arg366Trp) has been reported to ClinVar as Pathogenic by both GeneDx and Invitae, further suggesting that the p.Arg366 residue is important for KCNQ1 protein function. Other missense variants +/- 5 amino acids have also been submitted to ClinVar as disease-causing. According to the Invitae report: Experimental studies have shown that this missense variant decreases the affinity of the KCNQ1 protein for PIP2, reducing the channel current amplitude. This variant has also been reported to lead to subcellular mislocalization of the KCNQ1 protein (PMID: 15935335, 19934648 , 23861489). We did not review this literature. This is a nonconservative amino acid change, resulting in the replacement of a positively-charged Arginine with a polar Glutamine. Residue 366 is in the cytoplasmic C-terminal domain of the protein (residues 349-676), in which missense variants are 22x more frequent in LQTS cases than in controls (Kapa et al. 2009). Arginine at this location is absolutely conserved across ~80 vertebrate species for which we have data. The surrounding residues are also absolutely conserved. This variant was reported in 1 non-Finnish European individual in the gnomAD database, which includes variant calls on ~140,000 individuals of European, African, Latino, South Asian, Ashkenazi, and East Asian descent. The phenotype of those individuals is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease. The curators made an effort to exclude individuals with severe pediatric diseases. No individual with p.Arg366Trp or p.Arg366Pro currently appears in gnomAD. -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2023	KCNQ1: PM1, PM2, PM5, PS4:Moderate, PP3, PS3:Supporting -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Sep 15, 2021	- -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	AiLife Diagnostics, AiLife Diagnostics	Apr 24, 2020	- -

Long QT syndrome 1 Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Aug 25, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Center For Human Genetics And Laboratory Diagnostics, Dr. Klein, Dr. Rost And Colleagues	Jun 09, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	Sep 01, 2022	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.97; 3Cnet: 0.96). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000052956). Different missense changes at the same codon (p.Arg366Leu, p.Arg366Trp) have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000052955 , VCV001185948). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -
Pathogenic, criteria provided, single submitter	clinical testing	Intergen, Intergen Genetics and Rare Diseases Diagnosis Center	Jul 18, 2023	- -

Long QT syndrome Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Oct 22, 2023	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 366 of the KCNQ1 protein (p.Arg366Gln). This variant is present in population databases (rs199473410, gnomAD 0.0009%). This missense change has been observed in individuals with long QT syndrome, hearing loss and prolonged QTc (PMID: 14678125, 23158531, 24689698, 25804018, 26669661). ClinVar contains an entry for this variant (Variation ID: 52956). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt KCNQ1 protein function. Experimental studies have shown that this missense change affects KCNQ1 function (PMID: 15935335, 19934648, 23861489). This variant disrupts the p.Arg366 amino acid residue in KCNQ1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9024139, 10973849, 15840476, 16556865, 22949429). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Oct 23, 2023	This missense variant replaces arginine with glutamine at codon 366 of the KCNQ1 protein. This variant is found within a highly conserved region (a.a.349-391) of the C-terminal cytoplasmic domain. Rare nontruncating variants in this region have been shown to be significantly overrepresented in individuals with long QT syndrome (PMID: 32893267). Functional studies have shown that this variant causes endoplasmic reticulum retention (PMID:15935335), affects the binding to phosphatidylinositol 4,5-bisphosphate (PIP2), results in decreased strength of PIP2-dependent coupling of the voltage-sensing domain and the pore domain and a reduction in channel current (PMID: 19934648, 23861489). This variant has been reported in over twenty families affected with long QT syndrome and more than half of them were from Turkish population (PMID: 10973849, 24363352, 24667783, 24689698, 25804018, 26669661, 28472724, 29037160, 32383558, 34860437). In these families, in addition to affected heterozygous carriers, this variant has also been observed in homozygous state in multiple individuals affected with long QT syndrome and congenital hearing loss (PMID: 34860437), in compound heterozygous state with a pathogenic splice variant in an individual affected with Jervell and Lange-Nielsen syndrome (PMID: 32383558), and in digenic heterozygous state with a known pathogenic SCN5A variant in an individual diagnosed with long QT syndrome at a young age (PMID: 25804018). This variant has been identified in 1/251240 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	May 24, 2022	- -
Pathogenic, criteria provided, single submitter	research	Dept of Medical Biology, Uskudar University	Jan 08, 2024	Criteria: PS3_Moderate, PS4_Strong, PM1, PM2, PP3 -

Jervell and Lange-Nielsen syndrome 1 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Clinical Genetics Laboratory, Region Ostergotland

Oct 09, 2017

PM2, PP1, PP3, PM5, PP5, PP4 -

Congenital long QT syndrome Other:1

not provided, no classification provided

literature only

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

-

This variant has been reported as associated with Long QT syndrome in the following publications (PMID:10973849;PMID:14678125;PMID:19716085;PMID:19934648;PMID:15935335). 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	Pathogenic	0.99
CardioboostArm	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.55
Cadd	Pathogenic	33
Dann	Pathogenic	1.0
DEOGEN2	Pathogenic	0.84	D;.
Eigen	Pathogenic	0.76
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.97	D;D
M_CAP	Pathogenic	0.96	D
MetaRNN	Pathogenic	0.97	D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.8	M;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.84	D
PROVEAN	Uncertain	-3.6	D;D
REVEL	Pathogenic	0.97
Sift	Uncertain	0.0020	D;D
Sift4G	Uncertain	0.0080	D;D
Polyphen		1.0	D;D
Vest4		0.88
MutPred		0.85		Loss of MoRF binding (P = 0.0141);.;
MVP		0.96
MPC		1.3
ClinPred		1.0	D
GERP RS		3.8
Varity_R		0.81
gMVP		0.88

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs199473410; hg19: chr11-2606506; COSMIC: COSV105843732;