11-2776997-C-T

Position:

• chr11-2776997-C-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1 PM5 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 Pathogenic.

• 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:10 O:1
• Conservation: PhyloP100: 4.48

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 14 ACMG points.

• PM1: In a region_of_interest Interaction with KCNE1 C-terminus (size 37) in uniprot entity KCNQ1_HUMAN there are 36 pathogenic changes around while only 1 benign (97%) in NM_000218.3
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-2776996-T-C is described in Lovd as [Pathogenic].
• 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 [Likely_pathogenic]. Clinvar id is 53006.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-2776997-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNQ1	NM_000218.3	c.1697C>T	p.Ser566Phe	missense_variant	14/16	ENST00000155840.12	NP_000209.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNQ1	ENST00000155840.12	c.1697C>T	p.Ser566Phe	missense_variant	14/16	1	NM_000218.3	ENSP00000155840.2
KCNQ1	ENST00000335475.6	c.1316C>T	p.Ser439Phe	missense_variant	14/16	1		ENSP00000334497.5
KCNQ1	ENST00000496887.7	c.1340C>T	p.Ser447Phe	missense_variant	14/16	5		ENSP00000434560.2
KCNQ1	ENST00000646564.2	c.1157C>T	p.Ser386Phe	missense_variant	9/11			ENSP00000495806.2

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

Gnomad4 AFR exome AF: 0.00

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: 0.00

Gnomad4 NFE exome AF: 0.0000108

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:10 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jan 12, 2022	PP3, PM1, PM2_supporting, PS4 -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 27, 2024	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) -
Likely pathogenic, no assertion criteria provided	clinical testing	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Dec 17, 2014	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). -

Long QT syndrome 1 Pathogenic:2

Likely pathogenic, no assertion criteria provided	research	Division of Human Genetics, Children's Hospital of Philadelphia	Mar 10, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	May 21, 2020	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 -

Long QT syndrome Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 30, 2020	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Sep 26, 2023	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; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 53006). 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. 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; Invitae), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. -

not specified Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

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

Apr 18, 2016

- -

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

Likely pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Nov 18, 2021

- -

Cardiovascular phenotype Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 22, 2024

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

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: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
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;.;.
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

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