11-2776006-C-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PP3_Strong PP5_Very_Strong

The NM_000218.3(KCNQ1):c.1637C>T(p.Ser546Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000352 in 1,421,670 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 (★★). Synonymous variant affecting the same amino acid position (i.e. S546S) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000035 (0 hom.)
• Consequence: KCNQ1 NM_000218.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7 O:1
• Conservation: PhyloP100: 5.66

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 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 9 uncertain in NM_000218.3
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.986
• PP5: Variant 11-2776006-C-T is Pathogenic according to our data. Variant chr11-2776006-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 53000.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-2776006-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNQ1	NM_000218.3	c.1637C>T	p.Ser546Leu	missense_variant	13/16	ENST00000155840.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNQ1	ENST00000155840.12	c.1637C>T	p.Ser546Leu	missense_variant	13/16	1	NM_000218.3	P1
KCNQ1	ENST00000335475.6	c.1256C>T	p.Ser419Leu	missense_variant	13/16	1
KCNQ1	ENST00000496887.7	c.1280C>T	p.Ser427Leu	missense_variant	13/16	5
KCNQ1	ENST00000646564.2	c.1097C>T	p.Ser366Leu	missense_variant	8/11

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000352 AC: 5 AN: 1421670 Hom.: 0 Cov.: 32 AF XY: 0.00000285 AC XY: 2 AN XY: 702954

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: 0.00000458

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Aug 31, 2023	Not observed at significant frequency in large population cohorts (gnomAD); Functional studies suggest that p.(S546L) results in reduced IKs currents in heterologous cells (Yang et al., 2009); 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: 19841300, 26675252, 15840476, 31737537, 25037568, 15176425, 19716085, 22949429, 15466642, 27026747, 26063740, 21131640, 21185501, 22456477, 27535533, 26582918, 32383558, 17905336, 32901917, 22581653, 36505078, RidaM2023[Preprint], 34505893, 19808498) -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Feb 10, 2023	PP3, PM2_supporting, PS3, PS4 -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 10, 2014	- -

Long QT syndrome 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

3billion

Jan 03, 2022

Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000053000, PMID:15466642, PS1_S). The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID: 22456477, 17905336, 22949429, 26675252, PS4_S). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.94, 3CNET: 0.993, PP3_P). A missense variant is a common mechanism associated with Long QT syndrome 1 (PP2_P). It is not observed in the gnomAD v2.1.1 dataset (PM2_M).Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -

Long QT syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jan 20, 2024

This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 546 of the KCNQ1 protein (p.Ser546Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with long QT syndrome (PMID: 15466642, 15840476, 17905336, 19716085, 22456477, 22949429, 26675252, 27026747; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 53000). 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: 19808498, 25037568). For these reasons, this variant has been classified as Pathogenic. -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 13, 2023

The p.S546L pathogenic mutation (also known as c.1637C>T), located in coding exon 13 of the KCNQ1 gene, results from a C to T substitution at nucleotide position 1637. The serine at codon 546 is replaced by leucine, an amino acid with dissimilar properties, and is located in the C-terminal region of the protein. This alteration has been reported in multiple individuals with long QT syndrome (LQTS) (Choi G et al. Circulation 2004 Oct; 110(15):2119-24; Chung SK et al. Heart Rhythm 2007 Oct; 4(10):1306-14; Albertella L et al. Arch. Dis. Child. 2011 Aug; 96(8):704-7). Furthermore, the p.S546L variant disrupts KCNQ1 function in in vitro electrophysiological assays (Yang T et al. Circ Arrhythm Electrophysiol 2009 Aug; 2(4):417-26; Dvir M, J. Cell. Sci. 2014 Sep; 127(Pt 18):3943-55). 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 supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Cardiac arrhythmia Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Jun 06, 2019

This missense variant is located in the C-terminal cytoplasmic domain of the KCNQ1 protein that interacts with the KCNE1 protein. Computational prediction tools and conservation analyses suggest that this variant may have deleterious impact on the protein function. Computational splicing tools suggest that this variant may not impact RNA splicing. Experimental studies have shown that this variant may impair the channel function and disrupt interaction with the KCNE1 protein (PMID: 19808498, 25037568). This variant has been reported in 9 individuals affected with long QT syndrome (PMID: 17905336, 22456477, 22949429, 26675252), in over 10 individuals suspected of having long QT syndrome (PMID: 15840476, 19716085, 27026747), and in an individual affected with sudden death (PMID: 15466642). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on available evidence, this variant is classified as Likely 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:15176425;PMID:15466642;PMID:15840476;PMID:17905336;PMID:19716085;PMID:19808498;PMID:19841300). 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	0.52	D
BayesDel_noAF	Pathogenic	0.51
Cadd	Pathogenic	32
Dann	Pathogenic	1.0
DEOGEN2	Pathogenic	0.99	D;.;.
Eigen	Pathogenic	0.71
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	1.0	D;D;D
M_CAP	Pathogenic	0.95	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Pathogenic	0.98	D
MutationAssessor	Pathogenic	3.0	M;.;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.79	T
PROVEAN	Pathogenic	-5.0	D;.;D
REVEL	Pathogenic	0.94
Sift	Pathogenic	0.0	D;.;D
Sift4G	Pathogenic	0.0010	D;.;D
Polyphen		0.99	D;.;D
Vest4		0.95
MutPred		0.90		Gain of helix (P = 0.0696);.;.;
MVP		0.98
MPC		1.1
ClinPred		1.0	D
GERP RS		3.8
Varity_R		0.82
gMVP		0.98

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs199473480; hg19: chr11-2797236; COSMIC: COSV105028479; COSMIC: COSV105028479;