11-2585275-C-T

Position:

• chr11-2585275-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000218.3(KCNQ1):​c.1096C>T​(p.Arg366Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,648 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. R366P) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: KCNQ1 NM_000218.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:14 O:1
• Conservation: PhyloP100: 0.635

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 18 ACMG points.

• PM1: In a helix (size 25) in uniprot entity KCNQ1_HUMAN there are 25 pathogenic changes around while only 1 benign (96%) in NM_000218.3
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-2585276-G-C is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.982
• PP5: Variant 11-2585275-C-T is Pathogenic according to our data. Variant chr11-2585275-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 52955.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-2585275-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.1096C>T	p.Arg366Trp	missense_variant	8/16	ENST00000155840.12	NP_000209.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNQ1	ENST00000155840.12	c.1096C>T	p.Arg366Trp	missense_variant	8/16	1	NM_000218.3	ENSP00000155840.2
KCNQ1	ENST00000335475.6	c.715C>T	p.Arg239Trp	missense_variant	8/16	1		ENSP00000334497.5
KCNQ1	ENST00000496887.7	c.771+1730C>T		intron_variant		5		ENSP00000434560.2
KCNQ1	ENST00000646564.2	c.588+1730C>T		intron_variant				ENSP00000495806.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461648 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727142

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:14 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Long QT syndrome 1 Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	Center For Human Genetics And Laboratory Diagnostics, Dr. Klein, Dr. Rost And Colleagues	Jan 16, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	Feb 25, 2020	- -
Pathogenic, criteria provided, single submitter	research	HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	Feb 10, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Molecular Genetics Laboratory - Cardiogenetics, CHU de Nantes	Aug 01, 2023	- -
Pathogenic, no assertion criteria provided	clinical testing	Bioscientia Institut fuer Medizinische Diagnostik GmbH, Sonic Healthcare	Feb 19, 2018	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Petrovsky National Research Centre of Surgery, The Federal Agency for Scientific Organizations	Oct 12, 2023	We observed a heterozygous c.1096C>T (p.Arg366Trp) genetic variant in the KCNQ1 gene on WES data in a 7-month-old male proband diagnosed with long QT syndrome. ClinVar contains an entry for this variant (Variation ID: 52955) observed in patients with the consistent phenotype. This variant is not present in gnomAD database and located in a mutational hot spot and/or critical and well-established functional domain (PM1_strong according to Walsh R. et al. (PMID: 32893267). Multiple computational resources predict deleterious effect of p.Arg366Trp genetic variant. Functional studies in cultured mammalian cells and/or Xenopus oocytes demonstrate that p.Arg366Trp impairs calmodulin binding and disrupts channel expression and function (PMID: 16556865). For these reasons, this variant has been classified as Likely Pathogenic. -

not provided Pathogenic:3

Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 10, 2022	Not observed at significant frequency in large population cohorts (gnomAD); Functional studies in cultured mammalian cells and/or Xenopus oocytes demonstrate that R366W impairs calmodulin binding and disrupts channel expression and function (Shamgar et al., 2006); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Reported in ClinVar as pathogenic or likely pathogenic (ClinVar Variant ID#52955; ClinVar); This variant is associated with the following publications: (PMID: 24357532, 26063740, 27231019, 9693036, 22949429, 16556865, 25525159, 15466642, 19716085, 10220146, 14678125, 12388934, 24606995, 26669661, 31737537, 31447099, 29790872, 29740400, 30508507, 34135346, 34691145, 29497013) -
Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

Long QT syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 23, 2023	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 366 of the KCNQ1 protein (p.Arg366Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with long QT syndrome (PMID: 9693036, 15466642, 19716085, 19841300, 22949429, 24357532). ClinVar contains an entry for this variant (Variation ID: 52955). 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: 16556865). 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, 16556865, 19934648). 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	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 20, 2024	Variant summary: KCNQ1 c.1096C>T (p.Arg366Trp) results in a non-conservative amino acid change in 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 251240 control chromosomes. c.1096C>T has been reported in the literature in multiple individuals affected with Long QT Syndrome, including segregation within families (examples: Imboden_2006, Allegue_2011). These data indicate that the variant is very likely to be associated with disease. At least one publication reports the variant to affect protein function (Shagmar_2006). The following publications have been ascertained in the context of this evaluation (PMID: 17192539, 21499742, 16556865). ClinVar contains an entry for this variant (Variation ID: 52955). Based on the evidence outlined above, the variant was classified as pathogenic. -

Congenital long QT syndrome Pathogenic:1 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:9693036;PMID:10220146;PMID:11668638;PMID:14678125;PMID:15466642;PMID:15840476;PMID:16937190;PMID:19716085;PMID:19841300;PMID:10090529). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jul 24, 2017	The p.Arg366Trp variant in KCNQ1 has been reported in >12 individuals with long QT syndrome (Splawski 1998, Choi 2004, Kapplinger 2009, Kapa 2009, Giudicessi 20 12, and Torekov 2014) and has also been reported by other clinical laboratories in ClinVar (Variation ID 52955). This variant was absent from large population s tudies. In vitro functional studies provide some evidence that the p.Arg366Trp v ariant may impact protein function (Shamgar 2006). Computational prediction tool s and conservation analysis suggest that this variant may impact the protein. In summary, although additional studies are required to fully establish its clinic al significance, the p.Arg366Trp variant meets criteria to be likely pathogenic for autosomal dominant long QT syndrome. ACMG/AMP Criteria applied: PM2, PS4_Mo derate, PS3_Supporting, PP3. -

Jervell and Lange-Nielsen syndrome 1 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Institute of Human Genetics, University of Leipzig Medical Center

Aug 21, 2024

Criteria applied: PM5_STR,PM2_SUP,PP3 -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 29, 2021

The p.R366W pathogenic mutation (also known as c.1096C>T), located in coding exon 8 of the KCNQ1 gene, results from a C to T substitution at nucleotide position 1096. The arginine at codon 366 is replaced by tryptophan, an amino acid with dissimilar properties. This alteration has been reported multiple times in unrelated individuals reported to have long QT syndrome (LQTS) (Splawski I et al. Genomics. 1998;51(1):86-97; Choi G et al. Circulation. 2004;110(15):2119-24; Itoh H et al. Heart Rhythm. 2010;7(10):1411-8; Giudicessi JR. et al. Circ Cardiovasc Genet. 2012;5(5):519-28; Torekov SS et al. Diabetes. 2014;63(4):1315-25). One in vitro study reported this alteration to result in impaired binding to calmodulin, altered ion channel kinetics, and reduced cell surface expression (Shamgar L et al. Circ Res. 2006;98(8):1055-63). In addition, other alterations affecting the same amino acid (p.R366P (c.1097G>C) and p.R366Q (c.1097G>A)) have also been reported in association with LQTS (Splawski I et al. Circulation. 2000;102(10):1178-85). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.49
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.93	D;.
Eigen	Uncertain	0.31
Eigen_PC	Benign	0.17
FATHMM_MKL	Benign	0.60	D
LIST_S2	Pathogenic	0.98	D;D
M_CAP	Pathogenic	0.93	D
MetaRNN	Pathogenic	0.98	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.8	M;.
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-7.3	D;D
REVEL	Pathogenic	0.92
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0010	D;D
Polyphen		1.0	D;D
Vest4		0.93
MutPred		0.84		Loss of disorder (P = 0.0061);.;
MVP		0.97
MPC		1.2
ClinPred		0.99	D
GERP RS		0.65
Varity_R		0.90
gMVP		0.92

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs199473411; hg19: chr11-2606505;