11-2776997-C-T

Variant names:

• chr11-2776997-C-T
• rs199472804
• NM_000218.3:c.1697C>T

Variant summary

Our verdict is Pathogenic. The variant received 15 ACMG points: 15P and 0B. PM1 PM5 PP2 PP3_Moderate PP5_Very_Strong

The NM_000218.3(KCNQ1):​c.1697C>T​(p.Ser566Phe) variant causes a missense change. The variant allele was found at a frequency of 0.00000821 in 1,461,820 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. S566P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000082 (0 hom.)
• Consequence: KCNQ1 NM_000218.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:12 O:1
• Conservation: PhyloP100: 4.48
• Publications: 16 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 15 ACMG points.

• PM1: In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 19 uncertain in NM_000218.3
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-2776997-C-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 53005.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 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, 0.903
• PP5: Variant 11-2776997-C-T is Pathogenic according to our data. Variant chr11-2776997-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 53006.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.1697C>T	p.Ser566Phe	missense_variant	Exon 14 of 16	ENST00000155840.12	NP_000209.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNQ1	ENST00000155840.12	c.1697C>T	p.Ser566Phe	missense_variant	Exon 14 of 16	1	NM_000218.3	ENSP00000155840.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000821 AC: 12 AN: 1461820 Hom.: 0 Cov.: 32 AF XY: 0.0000124 AC XY: 9 AN XY: 727212

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86244

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53412

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

European-Non Finnish (NFE) AF: 0.0000108 AC: 12 AN: 1111972

Other (OTH) AF: 0.00 AC: 0 AN: 60390

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000865 Hom.: 0

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:12 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:4

Jan 12, 2022

Mayo Clinic Laboratories, Mayo Clinic

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PP3, PM1, PM2_supporting, PS4 -

Jun 27, 2024

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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; This variant is associated with the following publications: (PMID: 22949429, 22581653, 25525159, 17470695, 19841300, 19716085, 14678125, 22956155, 12388934, 23098067, 22456477, 27231019, 21131640, 23631430, 10973849) -

Dec 17, 2014

Stanford Center for Inherited Cardiovascular Disease, Stanford University

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. KCNQ1 p.Ser566Phe This variant has been reported in at least 9 unrelated cases, with no segregation data available. The variant was first reported by Splawski et al (2000) in 3 unrelated families with long QT syndrome. The cohort was recruited from North America and Europe. They do not specifically note that these patients are from the long QT registry but several of the authors on the paper lead the registry. Phenotype, ancestry, and segregation were not reported. Kapplinger et al (2009) reported the variant in 5 unrelated individuals who had long QT genetic testing at the PGxHealth/Familion laboratory. Of note in considering the cases reported by Kapplinger et al (2009) is the lack of phenotypic data on this cohort, the low yield of 36% (vs. 70% in cohorts with firm diagnoses of long QT), and the lack of clarity regarding which variants were seen with another variant (9% of the cohort had multiple variants). Zareba et al (2003) include two patients with this variant from the international long QT registry in a study on genotype-phenotype correlation (may overlap with the cases reported by Splawski et al). Kapa et al (2009) included one Caucasian patient with this variant in a study comparing variants in cases and controls, however that case may overlap with Kapplinger et al (2009) as the sample came from the Mayo, Familion, and Dutch cohots. Moss et al (2007) note three individuals with long QT who died suddenly and had this variant, however it is unclear whether those individuals are related. That sample was drawn from the international registry, the Dutch registry, and the Japanese registry, so these cases may overlap with Zareba et al (2003), Kapa et al (2009) and Splawski et al (2000) as well. The variant was also included in a paper by Ackerman’s group on variant classification, which likely overlaps prior reports (Guidicessi et al 2012). Albertella et al (2011) reported the variant in a child with long QT syndrome who had a water-related event. PolyPhen-2 predicts the variant to be probably damaging and mutation taster predicts it to be disease causing. While the serine at codon 566 is conserved across most species it is a phenylalanine (same as this variant) in chimps. Other variants at the same codon have been reported in association with long QT syndrome: p.Ser566Pro (Kapplinger et al 2009, Tester et al 2005), p.Ser566Tyr (Tester et al 2005). Variants at nearby codons have also been reported with long QT syndrome: p.Arg562Met (van Langen et al 2003, Moss et al 2007), p.Ile567Ser (Zareba et al 2003, Choi et al 2004, Tester et al 2005), p.Ile567Thr (Napolitano et al 2005, Kapplinger et al 2009), p.Gly568Ala (Chen et al 2003), p.Gly568Arg (Tester et al 2005, Kapplinger et al 2009), p.Lys569Glu (Kapplinger et al 2009), p.Ser571Leu (Kapplinger et al 2009). There is no variation at codon 566 in the NHLBI ESP, which currently includes variant calls from ~6500 individuals (as of Sept 30 2012). The variant is not listed in 1000 genomes (as of Sept 30 2012). The variant is listed in dbSNP (rs199472804), however the only submission is from a long QT clinical database. There is no population frequency data provided in dbSNP. The variant has not been observed in a total of 1500 published controls. Splawski et al (2000) did not observe the variant in 200 presumed healthy individuals. Kapplinger et al (2009) reported that the variant was not observed in 1,300 presumed healthy individuals (47% Caucasian, 26% African American, 11% Hispanic, 10% Asian, and 6% unknown/other). -

Dec 04, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The KCNQ1 c.1697C>T; p.Ser566Phe variant (rs199472804) is reported in the literature in numerous individuals affected with or suspected of long QT syndrome (Avari Silva 2016, Giudicessi 2012, Kapa 2009, Lieve 2013, Splawski 2000, Stattin 2012, Walsh 2021). This variant is also absent from the Genome Aggregation Database (v2.1.1), indicating it is not a common polymorphism. Additionally, other variants at this codon (c.1697C>A; p.Ser566Tyr) have been reported in individuals with long QT syndrome (Lieve 2013, Strand 2020, Tester 2005). Computational analyses predict that this variant is deleterious (REVEL: 0.83). Based on available information, this variant is considered to be likely pathogenic. References: Avari Silva JN et al. Implantable Loop Recorder Monitoring for Refining Management of Children With Inherited Arrhythmia Syndromes. J Am Heart Assoc. 2016 May 26;5(6):e003632. PMID: 27231019. Giudicessi JR et al. Phylogenetic and physicochemical analyses enhance the classification of rare nonsynonymous single nucleotide variants in type 1 and 2 long-QT syndrome. Circ Cardiovasc Genet. 2012 Oct 1;5(5):519-28. PMID: 22949429. Kapa S et al. Genetic testing for long-QT syndrome: distinguishing pathogenic mutations from benign variants. Circulation. 2009 Nov 3;120(18):1752-60. PMID: 19841300. Lieve KV et al. Results of genetic testing in 855 consecutive unrelated patients referred for long QT syndrome in a clinical laboratory. Genet Test Mol Biomarkers. 2013 Jul;17(7):553-61. PMID: 23631430. Splawski I et al. Spectrum of mutations in long-QT syndrome genes. KVLQT1, HERG, SCN5A, KCNE1, and KCNE2. Circulation. 2000 Sep 5;102(10):1178-85. PMID: 10973849. Stattin EL et al. Founder mutations characterise the mutation panorama in 200 Swedish index cases referred for Long QT syndrome genetic testing. BMC Cardiovasc Disord. 2012 Oct 25;12:95. PMID: 23098067. Strand S et al. Complex and Novel Arrhythmias Precede Stillbirth in Fetuses With De Novo Long QT Syndrome. Circ Arrhythm Electrophysiol. 2020 May;13(5):e008082. PMID: 32421437. Tester DJ et al. Compendium of cardiac channel mutations in 541 consecutive unrelated patients referred for long QT syndrome genetic testing. Heart Rhythm. 2005 May;2(5):507-17. PMID: 15840476. Walsh R et al. Enhancing rare variant interpretation in inherited arrhythmias through quantitative analysis of consortium disease cohorts and population controls. Genet Med. 2021 Jan;23(1):47-58. PMID: 32893267. -

Long QT syndrome Pathogenic:3

Dec 06, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces serine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 566 of the KCNQ1 protein (p.Ser566Phe). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with long QT syndrome (PMID: 10973849, 14678125, 17470695, 19716085, 21131640, 22456477, 22949429, 23098067, 27231019; internal data). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 53006). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on KCNQ1 protein function. This variant disrupts the p.Ser566 amino acid residue in KCNQ1. Other variant(s) that disrupt this residue have been observed in individuals with KCNQ1-related conditions (PMID: 15840476, 19716085; internal data), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. -

Nov 30, 2020

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: KCNQ1 c.1697C>T (p.Ser566Phe) results in a non-conservative amino acid change located in the Potassium channel, voltage dependent, KCNQ, C-terminal domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251096 control chromosomes. c.1697C>T has been reported in the literature in multiple individuals and families affected with Long QT Syndrome (Earle_2013, Albertella_2011, Kapplinger_2009, Lieve_2013, Splawski_2000, Zareba_2003, etc). These data indicate that the variant is very likely to be associated with disease. However one clinical lab via ClinVar has reported possible non-segregation with disease observed in at least two families tested. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Other variants at the same codon position have also been reported in association with LQTS in HGMD (S566P, S566Y). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likley pathogenic. -

Feb 06, 2025

Molecular Genetics, Royal Melbourne Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change in KCNQ1 is predicted to replace serine with phenylalanine at codon 566, p.(Ser566Phe). The serine residue is highly conserved (100 vertebrates, Multiz Alignments) and is located in the C-terminus in an region that interacts with KCNE1. This region (amino acids 509-575) is defined as a mutational hotspot (PMID: 32893267). There is a large physicochemical difference between serine and phenylalanine. The highest population minor allele frequency in the population database gnomAD v4.1 is 0.001% (12/1,179,990 alleles) in the European (non-Finnish) population. This variant has been reported in multiple probands with long QT syndrome and segregates with disease in one family (PMID: 19841300, 27231019, 32893267, 37445499; ClinVar: SCV000074028.14, SCV001714960.2, SCV000234519.9, SCV005399121.1). Computational evidence predicts a deleterious effect for the missense substitution (REVEL = 0.830). Another missense variant, c.1697C>A, p.(Ser566Tyr) in the same codon has been classified as likely pathogenic/pathogenic (ClinVar ID: 53005). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.7.1, this variant is classified as PATHOGENIC. Following criteria are met: PS4, PM1_Strong, PM2_Supporting, PP1. -

Long QT syndrome 1 Pathogenic:2

May 21, 2020

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as Pathogenic. Following criteria are met: 0103 - Both loss- and gain-of-function are known mechanisms of disease for this gene (OMIM). (N) 0108 - This gene is known to be associated with both recessive and dominant disease (OMIM). (N) 0112 - Variants in this gene are known to have reduced penetrance (OMIM). (N) 0200 - Variant is predicted to result in a missense amino acid change from serine to phenylalanine (exon 14). (N) 0251 - Variant is heterozygous. (N) 0301 - Variant is absent from gnomAD. (P) 0502 - Missense variant with conflicting in silico predictions and moderate conservation. (N) 0600 - Variant is located in an annotated domain or motif (C-terminal domain which interacts with KCNE1 C-termius; UnitProt, PDB). (N) 0703 - Comparable variants have moderate previous evidence for pathogenicity. Two different variants in the same codon resulting in a change to a tyrosine and a proline have been shown to cause long QT (Cardiac Family Database, PMID: 19716085). (P) 0801 - Strong previous evidence of pathogenicity in unrelated individuals. This variant has been previously reported as pathogenic in multiple patients with long QT (ClinVar, Cardiac Family Database, PMID: 10973849, 14678125, 17470695, 19716085, 23098067). (P) 1208 - Inheritance information for this variant is not currently available. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign -

Mar 10, 2016

Division of Human Genetics, Children's Hospital of Philadelphia

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

not specified Pathogenic:1

Apr 18, 2016

Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

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 Pathogenic:1

Nov 18, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiovascular phenotype Pathogenic:1

Feb 22, 2024

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.S566F variant (also known as c.1697C>T), located in coding exon 14 of the KCNQ1 gene, results from a C to T substitution at nucleotide position 1697. The serine at codon 566 is replaced by phenylalanine, an amino acid with highly dissimilar properties, located in the C-terminal cytoplasmic region. This variant has been reported in several long QT syndrome (LQTS) cohorts (Splawski I et al. Circulation. 2000;102:1178-85; Kapa S et al. Circulation. 2009;120:1752-60; Albertella L et al. Arch Dis Child. 2011;96:704-7; Giudicessi JR et al. Circ Cardiovasc Genet. 2012;5:519-28; Stattin EL et al. BMC Cardiovasc Disord. 2012;12:95). Other variants affecting this codon (p.S566Y, p.S566P) have also been detected in LQTS cohorts; however, details were limited (Kapplinger JD. Heart Rhythm. 2009 Sep;6(9):1297-303). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be 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:19841300;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	Pathogenic	0.93
CardioboostArm	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.51	D
BayesDel_noAF	Pathogenic	0.49
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.91	D;.;.
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.96	D;D;D
M_CAP	Pathogenic	0.84	D
MetaRNN	Pathogenic	0.90	D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.3	M;.;.
PhyloP100		4.5
PrimateAI	Uncertain	0.71	T
PROVEAN	Uncertain	-2.9	D;.;D
REVEL	Pathogenic	0.83
Sift	Uncertain	0.0070	D;.;D
Sift4G	Uncertain	0.018	D;.;D
Polyphen		1.0	D;.;D
Vest4		0.89
MutPred		0.53		Loss of disorder (P = 0.0026);.;.;
MVP		0.97
MPC		1.2
ClinPred		0.97	D
GERP RS		4.0
Varity_R		0.72
gMVP		0.99
Mutation Taster		=1/99	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs199472804; hg19: chr11-2798227; COSMIC: COSV50104204; COSMIC: COSV50104204;