rs199473410

Variant names:

• chr11-2585276-G-A
• rs199473410
• NM_000218.3:c.1097G>A

Your query was ambiguous. Multiple possible variants found:

• chr11-2585276-G-A
• chr11-2585276-G-C
• chr11-2585276-G-T

Variant summary

Our verdict is Pathogenic. The variant received 17 ACMG points: 17P and 0B. PM1 PM5 PP2 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. R366W) 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:19 O:1
• Conservation: PhyloP100: 7.50
• Publications: 18 publications found

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 Gene-Disease associations (from GenCC):

• long QT syndrome

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• long QT syndrome 1

  Inheritance: AD, AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• Jervell and Lange-Nielsen syndrome

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• Jervell and Lange-Nielsen syndrome 1

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), G2P
• atrial fibrillation, familial, 3

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• short QT syndrome

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: ClinGen, Orphanet
• short QT syndrome type 2

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• familial atrial fibrillation

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Jervell and Lange-Nielsen syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• hypertrophic cardiomyopathy

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Pathogenic. The variant received 17 ACMG points.

• PM1: In a hotspot region, there are 17 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 15 uncertain in NM_000218.3
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-2585275-C-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 52955.Status of the report is reviewed_by_expert_panel, 3 stars.
• 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.
• 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 Pathogenic/Likely_pathogenic. ClinVar VariationId is 52956.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNQ1	NM_000218.3	c.1097G>A	p.Arg366Gln	missense_variant	Exon 8 of 16	ENST00000155840.12	NP_000209.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNQ1	ENST00000155840.12	c.1097G>A	p.Arg366Gln	missense_variant	Exon 8 of 16	1	NM_000218.3	ENSP00000155840.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251240 AF XY: 0.00

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 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

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39696

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53220

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000540 AC: 6 AN: 1111970

Other (OTH) AF: 0.00 AC: 0 AN: 60384

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:19 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:9

Apr 21, 2017

Stanford Center for Inherited Cardiovascular Disease, Stanford University

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: provider interpretation

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.

Clinical Genetics, Academic Medical Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

Nov 06, 2020

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PS3, PS4, PP1_Strong, PM2_Supporting, PM5, PP3, PP4

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

Sep 15, 2021

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nov 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

KCNQ1: PM1, PM2, PM5, PS4:Moderate, PP3, PS3:Supporting

Mar 13, 2024

Clinical Genetics Laboratory, Skane University Hospital Lund

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jun 17, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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)

Apr 24, 2020

AiLife Diagnostics, AiLife Diagnostics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Long QT syndrome 1 Pathogenic:4

Jun 09, 2021

MVZ Martinsried, Medicover Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jul 18, 2023

Intergen, Intergen Genetics and Rare Diseases Diagnosis Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Sep 01, 2022

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Aug 25, 2022

MGZ Medical Genetics Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Long QT syndrome Pathogenic:4

May 24, 2022

Genetics and Molecular Pathology, SA Pathology

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Apr 24, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 with a positive predictive value of 95%. 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.

Jan 08, 2024

Dept of Medical Biology, Uskudar University

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

Criteria: PS3_Moderate, PS4_Strong, PM1, PM2, PP3

Oct 23, 2023

All of Us Research Program, National Institutes of Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Jervell and Lange-Nielsen syndrome 1 Pathogenic:1

Oct 09, 2017

Clinical Genetics Laboratory, Region Ostergotland

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM2, PP1, PP3, PM5, PP5, PP4

Cardiac arrhythmia Pathogenic:1

Oct 21, 2024

Color Diagnostics, LLC DBA Color Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

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: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;.
PhyloP100		7.5
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
Vest4		0.88
ClinPred		1.0	D
GERP RS		3.8
Varity_R		0.81
gMVP		0.88
Mutation Taster		=9/91	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs199473410; hg19: chr11-2606506; COSMIC: COSV105843732;