11-2570719-G-T

Position:

• chr11-2570719-G-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.569G>T​(p.Arg190Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. R190Q) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: KCNQ1 NM_000218.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:10 O:1
• Conservation: PhyloP100: 9.36

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 6) in uniprot entity KCNQ1_HUMAN there are 13 pathogenic changes around while only 1 benign (93%) 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 chr11-2570719-G-A is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.991
• PP5: Variant 11-2570719-G-T is Pathogenic according to our data. Variant chr11-2570719-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 67084.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-2570719-G-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNQ1	NM_000218.3	c.569G>T	p.Arg190Leu	missense_variant	3/16	ENST00000155840.12	NP_000209.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNQ1	ENST00000155840.12	c.569G>T	p.Arg190Leu	missense_variant	3/16	1	NM_000218.3	ENSP00000155840.2
KCNQ1	ENST00000335475.6	c.188G>T	p.Arg63Leu	missense_variant	3/16	1		ENSP00000334497.5
KCNQ1	ENST00000496887.7	c.308G>T	p.Arg103Leu	missense_variant	4/16	5		ENSP00000434560.2
KCNQ1	ENST00000646564.2	c.478-12716G>T		intron_variant				ENSP00000495806.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000401 AC: 1 AN: 249462 Hom.: 0 AF XY: 0.00000739 AC XY: 1 AN XY: 135274

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 SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000885

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:10 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Long QT syndrome 1 Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Feb 27, 2023	_x000D_ Criteria applied: PM5_STR, PS4_MOD, PM1, PM2_SUP, PP3 -
Pathogenic, criteria provided, single submitter	clinical testing	Center For Human Genetics And Laboratory Diagnostics, Dr. Klein, Dr. Rost And Colleagues	Apr 04, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Sep 02, 2022	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Dominant negative, loss of function and gain of function are known mechanisms of disease in this gene. Gain of function variants result exclusively in short QT syndrome (MIM#609621), while dominant negative and loss of function variants can cause long QT syndrome (LQTS, MIM#192500), atrial fibrillation (MIM#607554) and Jervell and Lange-Nielsen syndrome (JLNS, MIM#220400) (OMIM, PMIDs: 19632626, 28438721). (I) 0108 - This gene is known to be associated with both recessive and dominant disease. JLNS is characterized by congenital, bilateral deafness and variable degrees of QT prolongation, and is the only condition caused by biallelic variants (PMID: 28438721). (I) 0112 - The condition associated with this gene has incomplete penetrance (OMIM, PMID: 20301308). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to leucine. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v2) <0.001 for a condition (1 heterozygote, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v3) (highest allele: 3 heterozygotes, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated ion transporter domain (DECIPHER) in the S2-S3 intracellular linker region. (I) 0701 - Other missense variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. Two alternative changes (p.Arg190Gln, p.Arg190Trp) have been reported as pathogenic in heterozygous individuals with long QT syndrome (LQTS), or homozygous individuals with Jervell and Lange-Nielsen syndrome (JLNS) (ClinVar). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported in multiple heterozygous individuals with LQTS, or homozygous individuals with JLNS (ClinVar, PMID: 19716085, 20138589). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Fuctional study has demonstrated that this variant impairs PIP2 regulation of the potassium channel (PMID: 24947509). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 07, 2017	The R190L pathogenic variant in the KCNQ1 gene has been reported multiple times in association with LQTS (Kapplinger et al., 2009; Kanovsky et al., 2010; Andrsova et al., 2012; Crehalet et al., 2012; Wang et al., 2015). Kanovsky et al. (2010) identified the R190L variant on both KCNQ1 alleles in two siblings with severe LQTS, one of whom had sub-clinical, bilateral hearing impairment that the authors termed incomplete" Jervell Lange-Nielsen syndrome. In the same study, the heterozygous parents of these two siblings had normal QT intervals at rest, but each parent had QT prolongation during stress testing (Kanovsky et al., 2010). R190L has been reported in combination with a KCNQ1 splice variant in a young male patient with LQTS (Crehalet et al., 2012). Additionally, Wang et al. (2015) identified R190L in conjunction with variants in the MYH7, MYLK2, and TMEM70 genes among four individuals in a Chinese family with overlapping phenotypes of LQTS and hypertrophic cardiomyopathy. R190L was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, and was not observed with any significant frequency in the Exome Aggregation Consortium (ExAC) data set.The R190L variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. Moreover, this substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Functional studies conducted by Eckey et al. (2014) demonstrated that R190L impairs phosphatidylinositol 4,5-bisphosphate (PIP2) regulation of ion channels, presumptively leading to ion channel dysfunction and LQTS phenotype. Finally, missense pathogenic variants in nearby residues, as well as in the same residue (G186S, R190W, R190Q) have been reported in the Human Gene Mutation Database in association with LQTS (Stenson et al., 2014), further supporting the functional importance of this region of the protein." -
Likely pathogenic, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	May 03, 2023	PP3, PM2_SUP -
Likely pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jul 29, 2024	PP1_moderate, PP3, PM2, PM3_supporting, PM5, PS3_supporting, PS4_moderate -

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:19716085;PMID:20138589). 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	Mar 22, 2019	The p.Arg190Leu variant in KCNQ1 has been reported in 1 individual referred for LQTS genetic testing (Kapplinger 2009). In addition, it was identified in the homozygous state in 2 sisters from a consanguineous family with a severe presentation of LQTS, one of whom had subclinical hearing loss. Their heterozygous parents were clinically unaffected, but both had prolonged QT interval during a stress test (Kanovsky 2010). It has also been identified in 1/113014 European chromosomes by gnomAD (http://gnomad.broadinstitute.org) and has been reported in ClinVar (Variation ID # 67084). In vitro functional studies and computational tools support an impact on protein function (Eckey 2014)). In addition, two other variants involving this codon (p.Arg190Gln and p.Arg190Trp) have been identified in individuals with LQTS. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant LQTS. ACMG/AMP criteria applied: PM2, PM5, PP3, PS3_Supporting, PS4_Supporting. -

Long QT syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 13, 2023

This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 190 of the KCNQ1 protein (p.Arg190Leu). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individuals with long QT Syndrome (PMID: 19716085, 20138589, 31737537, 32383558; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 67084). 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. Experimental studies have shown that this missense change affects KCNQ1 function (PMID: 24947509). This variant disrupts the p.Arg190 amino acid residue in KCNQ1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 8528244, 10376919, 10728423, 20660394). 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. -

Cardiovascular phenotype Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 25, 2022

The p.R190L variant (also known as c.569G>T), located in coding exon 3 of the KCNQ1 gene, results from a G to T substitution at nucleotide position 569. The arginine at codon 190 is replaced by leucine, an amino acid with dissimilar properties. In a study of long QT syndrome (LQTS) clinical genetic testing, this alteration was reported in one patient; however, clinical details were limited (Kapplinger JD et al. Heart Rhythm, 2009 Sep;6:1297-303). This alteration was also reported in homozygous state in two sisters with LQTS, one of whom was also revealed to have subclinical bilateral sensorineural hearing impairment. Their asymptomatic parents were both heterozygous for this alteration and showed prolonged QTc upon stress test (Kanovsky J et al. Heart Rhythm, 2010 Apr;7:531-3). In vitro studies suggested that this alteration would affect channel activity (Eckey K et al. J. Biol. Chem., 2014 Aug;289:22749-58). 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. -

Cardiac arrhythmia Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Feb 01, 2023

This missense variant replaces arginine with leucine at codon 190 of the KCNQ1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). A functional study has suggested that this missense variant may affect potassium channel function (PMID: 24947509). This variant has been reported in heterozygous state in an individual suspected of having long QT syndrome (PMID: 19716085). This variant has also been reported in homozygosity in two sisters, one affected with Jervell and Lange-Nielsen syndrome and the other one with Romano-Ward syndrome. Their heterozygous parents were asymptomatic but showed pathological QTs during the stress test (PMID: 20138589). This variant has been identified in 1/249462 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Different missense variants occurring at the same codon, p.Arg190Gln and p.Arg190Trp are known to be disease-causing (ClinVar variation ID: 3117, 53070), indicating that arginine at this position is important for KCNQ1 protein function. Based on available evidence, this variant is classified as Likely Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.56
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.99	.;D;.
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	1.0	D;D;D
M_CAP	Pathogenic	0.87	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.5	.;M;.
PrimateAI	Uncertain	0.73	T
PROVEAN	Pathogenic	-6.6	D;D;D
REVEL	Pathogenic	0.95
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	.;D;.
Vest4		0.99, 0.98
MutPred		0.94		.;Loss of methylation at R190 (P = 0.0273);.;
MVP		0.98
MPC		1.3
ClinPred		1.0	D
GERP RS		4.4
Varity_R		0.93
gMVP		0.98

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: rs120074178; hg19: chr11-2591949; COSMIC: COSV105843730;