Submissions for variant NM_000218.3(KCNQ1):c.728G>A (p.Arg243His)

gnomAD frequency: 0.00001  dbSNP: rs120074196

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Color Diagnostics, LLC DBA Color Health	RCV001841652	SCV001355488	pathogenic	Cardiac arrhythmia	2022-02-07	criteria provided, single submitter	clinical testing	This missense variant is located in the fourth segment (S4) of the transmembrane domain 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). Functional studies have shown that this variant causes a defect in protein trafficking (PMID:15935335), reduced binding affinity for PIP2 (PMID: 15746441, 24681627), and decreased current compared to wild type (PMID: 10090886, 15746441, 19843919, 24681627). This variant has been reported in at least eight unrelated heterozygous individuals affected with long QT syndrome (PMID: 15028050, 19843919, 32893267). This variant has been also reported in homozygous or in compound heterozygous state with a known pathogenic KCNQ1 variant in four unrelated individuals affected with Jervell and Lange-Nielsen Syndrome, a severe form of long QT syndrome that also involves hearing loss (PMID: 10090886, 10728423, 23400408, 26022593, 29037160). Four heterozygous relatives from these families and another unrelated heterozygous individual (PMID:19843919) were reported to be either asymptomatic or have a modestly prolonged QT interval, suggesting reduced penetrance. This variant has been identified in 2/280356 chromosomes in the general population by the Genome Aggregation Database (gnomAD). A different missense variant occurring at the same codon, p.Arg243Cys, is known to cause long QT syndrome (Clinvar variation ID: 53091), indicating that arginine at this position is important for KCNQ1 protein function. Based on the available evidence, this variant is classified as Pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001385528	SCV001585410	pathogenic	Long QT syndrome	2022-07-18	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 243 of the KCNQ1 protein (p.Arg243His). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg243 amino acid residue in KCNQ1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10973849, 12877697, 14678125, 15234419, 15466642, 15469540, 15840476, 17470695, 19716085, 19841300, 20167303). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects KCNQ1 function (PMID: 10090886, 11530100, 15746441, 15935335, 19843919, 24681627). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 53092). This missense change has been observed in individuals with Jervell and Lange-Nielsen syndrome (PMID: 10728423, 23400408, 26022593). 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.
3billion	RCV001807770	SCV002058535	pathogenic	Jervell and Lange-Nielsen syndrome 1	2022-01-03	criteria provided, single submitter	clinical testing	The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID: 26022593, 23400408, PS4_S). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.954, 3CNET: 0.984, PP3_P). A missense variant is a common mechanism associated with Jervell and Lange-Nielsen syndrome (PP2_P). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000007, PM2_M). A different missense change at the same codon has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000053091, PMID:10409658,16922724,19490272, PM5_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Ambry Genetics	RCV002381343	SCV002672919	likely pathogenic	Cardiovascular phenotype	2022-08-25	criteria provided, single submitter	clinical testing	The p.R243H variant (also known as c.728G>A), located in coding exon 5 of the KCNQ1 gene, results from a G to A substitution at nucleotide position 728. The arginine at codon 243 is replaced by histidine, an amino acid with highly similar properties. This alteration is located in the S4 transmembrane domain and has been reported in trans with another pathogenic KCNQ1 mutation in a proband with Jervell and Lange-Nielsen syndrome (JLNS) (Chouabe C et al. Cardiovasc. Res., 2000 Mar;45:971-80). This variant has also been detected in the homozygous state in multiple Turkish probands with JLNS, while some heterozygous relatives were reported to have QTc intervals within normal limits (Huang L et al. Cardiovasc. Res., 2001 Sep;51:670-80; Bostan O et al. Pediatr Cardiol, 2013 Feb;34:2063-7; Klç E et al. Turk. J. Pediatr.;56:542-5). General population frequency data for the Turkish population is limited and the possibility that this alteration is common in the Turkish subpopulation can not be excluded. This alteration has been identified in the heterozygous state in a patient with drug-induced long QT syndrome (Kobori A et al. J. Cardiovasc. Electrophysiol., 2004 Feb;15:190-9). A number of functional studies suggest that this alteration results in deficient protein function (Mohammad-Panah R et al. Am. J. Hum. Genet., 1999 Apr;64:1015-23; Chouabe C et al. Cardiovasc. Res., 2000 Mar;45:971-80; Huang L et al. Cardiovasc. Res., 2001 Sep;51:670-80; Wilson AJ et al. Cardiovasc. Res., 2005 Aug;67:476-86; Park KH et al. Circ. Res., 2005 Apr;96:730-9; Itoh H et al. Circ Arrhythm Electrophysiol, 2009 Oct;2:511-23). 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.
Dept of Medical Biology, Uskudar University	RCV003482908	SCV004022074	pathogenic	Jervell and Lange-Nielsen syndrome	2024-01-08	criteria provided, single submitter	research	Criteria: PS3_Moderate, PM1, PM2, PM3_Strong, PP3
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV003482908	SCV004847671	likely pathogenic	Jervell and Lange-Nielsen syndrome	2019-03-18	criteria provided, single submitter	clinical testing	The p.Arg243His variant in KCNQ1 has been reported in 4 individuals with Jervell and Lange-Nielsen syndrome (JLNS): It was identified in the homozygous state in 3 Turkish individuals from consanguineous families (Tyson 1997, Tyson 2000, Bostan 2013, Kılıç 2014) and in the compound heterozygous state in 1 French individual (Mohammad-Panah 1999, Chouabe 2000). Relatives who were heterozygous carriers of this variant were either clinically asymptomatic for LQTS or had a modestly prolonged QT interval (Larsen 1999, Ning 2003) suggesting reduced penetrance and variable expressivity. This variant has also been reported in one individual with long QT syndrome (LQTS; Kobori 2004, Itoh 2009). In vitro functional studies support an impact on protein function (Mohammad-Panah 1999, Chouabe 2000, Huang 2001, Itoh 2009. The p.Arg243His variant has been identified in 0.004% (1/24684) of African chromosomes and 0.003% (1/30584) of South Asian chromosomes by gnomAD (http://gnomad.broadinstitute.org) and is present in ClinVar (Variation ID: 53092). Computational prediction tools and conservation analysis suggest that this variant may impact the protein. 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 recessive JLNS (ACMG/AMP Criteria applied: PM2, PM3, PP3, PS3_Supporting), but its clinical significance in LQTS is uncertain (ACMG/AMP Criteria applied: PM2, PP3, PS3_Supporting).
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV004786324	SCV005399232	likely pathogenic	Long QT syndrome 1	2020-10-19	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.3, this variant is classified as likely 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 (GeneReviews, OMIM). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to histidine. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v2) <0.001 for a dominant condition (2 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (1 heterozygote, 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 voltage sensor S4 domain (PDB). (I) 0703 – Other missense variants comparable to the one identified in this case have moderate previous evidence for pathogenicity. p.(Arg243Cys) has been reported in multiple LQTS patients (PMIDs: 19716085, 15840476) and has three pathogenic entries in ClinVar. p.(Arg243Ile) has been identified in one LQTS patient (PMID: 15234419). p.(Arg243Pro) has been reported in a two day old infant with fetal and neonatal bradycardia in whom an additional KCNH2 missense variant was identified (PMID: 16922724). p.(Arg243Ser) has one VUS entry in ClinVar. (SP) 0802 - This variant has moderate previous evidence of pathogenicity in unrelated individuals. This variant has been identified in compound heterozygous or homozygous state in multiple JLNS patients and heterozygous carriers are reported to be asymptomatic (PMIDs: 29037160, 10728423, 11140949, 26022593). There is a single report of this variant in heterozygous state in a JLNS patient in whom the second variant was not yet determined (PMID: 10090886). Additionally, this variant has one VUS entry in ClinVar (clinical information is listed as arrhythmia). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Functional evidence indicated that this variant has a dominant-negative effect, causing a right shift in the steady-state activation curve and leads to an increased deactivation rate (PMID: 11530100). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I)
Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust	RCV000057742	SCV000089261	not provided	Congenital long QT syndrome		no assertion provided	literature only	This variant has been reported in the following publications (PMID:9482580;PMID:10090886;PMID:11530100;PMID:15028050;PMID:18174212;PMID:19843919;PMID:10728423;PMID:11140949;PMID:15935335;PMID:10409658;PMID:15746441).
PreventionGenetics, part of Exact Sciences	RCV004542713	SCV004784719	pathogenic	KCNQ1-related disorder	2023-11-19	no assertion criteria provided	clinical testing	The KCNQ1 c.728G>A variant is predicted to result in the amino acid substitution p.Arg243His. This variant was reported in the homozygous or compound heterozygous state with a second pathogenic KCNQ1 variant in at least three unrelated individuals with Jervell and Lange-Nielsen syndrome (Chouabe et al. 2000. PubMed ID: 10728423; Bostan et al. 2013. PubMed ID: 23400408; Kılıç et al. 2014. PubMed ID: 26022593). Of note, heterozygous carriers have been documented with a wide range of phenotypic variability, ranging from asymptomatic, borderline QTc interval, to a clinical diagnosis of long QT syndrome (Mohammad-Panah et al. 1999. PubMed ID: 10090886; Itoh et al. 2009. PubMed ID: 19843919; Bostan et al. 2013. PubMed ID: 23400408; Table S1, Schwartz et al. 2021. PubMed ID: 34505893; Saat et al. 2022. PubMed ID: 35703482). Functional studies support the pathogenicity of this variant (Chouabe et al. 2000. PubMed ID: 10728423; Huang et al. 2001. PubMed ID: 11530100; Park et al. 2005. PubMed ID: 15746441; Coyan et al. 2014. PubMed ID: 24681627). This variant is reported in 0.0041% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/11-2593287-G-A). This variant is interpreted as pathogenic.