Submissions for variant NM_000218.3(KCNQ1):c.805G>A (p.Gly269Ser)

dbSNP: rs120074193

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000182118	SCV000234421	pathogenic	not provided	2023-07-27	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies demonstrate a damaging effect as this variant may cause abnormal assembly and stability of the potassium channel and exert moderate dominant-negative suppression of the potassium channel (Verma et al., 2009; Wu et al., 2014; Wang et al., 2014); 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: 25348405, 20044973, 19808498, 27816319, 22677073, 29740400, 29439887, 15234419, 15176425, 18752142, 19841300, 9312006, 9386136, 10973849, 12051962, 12522251, 17470695, 31328865, 29151524, 25082577, 33087929, 10560595, 34319147, 32470535, 34505893, 24184248)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000477568	SCV000543295	pathogenic	Long QT syndrome	2024-01-22	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 269 of the KCNQ1 protein (p.Gly269Ser). This variant is present in population databases (rs120074193, gnomAD 0.003%). This missense change has been observed in individual(s) with long QT syndrome (PMID: 15176425, 15234419, 18752142, 24184248). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 3144). 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: 20044973, 24184248). This variant disrupts the p.Gly269 amino acid residue in KCNQ1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9312006, 9386136, 10973849, 12051962, 12522251, 17470695). 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.
Fulgent Genetics, Fulgent Genetics	RCV000762834	SCV000893193	pathogenic	Atrial fibrillation, familial, 3; Beckwith-Wiedemann syndrome; Long QT syndrome 1; Jervell and Lange-Nielsen syndrome 1; Short QT syndrome type 2	2018-10-31	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001002562	SCV001160534	pathogenic	not specified	2019-05-22	criteria provided, single submitter	clinical testing	The c.805G>A; p.Gly269Ser variant (rs120074193, ClinVarID 3144 ) was first reported in a 16-year-old asymptomatic boy, whose cousin passed out in a swimming pool due to a triggered cardiac event (Ackerman 1999). This patient's QT was measured at 470 ms. Since then, the p.Gly269Ser variant has been reported in patients with long QT syndrome, including at least four families, where the variant segregated with disease (Wu 2014, Fujii 2017). Additionally, other amino acid substitutions at this codon (p.Gly269Asp, p.Gly269Val) have been reported in individuals with LQTS and are considered pathogenic (Donger 1997, and ClinVar IDs: 3145 & 200899). This variant is only observed on one allele in the Genome Aggregation Database, indicating it is not a common polymorphism. The glycine at codon 269 is highly conserved in the transmembrane S5 domain, and functional studies demonstrate that the p.Gly269Ser variant causes a reduction in potassium ion current and protein stability (Wu 2014 and Verma 2010). Computational analyses by SIFT and PolyPhen-2 also predict that this variant is deleterious. Overall, this variant is considered to be pathogenic.
Ambry Genetics	RCV002408447	SCV002675873	pathogenic	Cardiovascular phenotype	2019-01-25	criteria provided, single submitter	clinical testing	The p.G269S pathogenic mutation (also known as c.805G>A), located in coding exon 6 of the KCNQ1 gene, results from a G to A substitution at nucleotide position 805. The glycine at codon 269 is replaced by serine, an amino acid with similar properties. This mutation has been detected in numerous individuals with long QT syndrome (LQTS), some demonstrating symptoms triggered by physical exertion such as swimming; segregation was reported in affected family members from several families (Ackerman MJ et al. Mayo Clin. Proc., 1999 Nov;74:1088-94; Chen S et al. Clin. Genet., 2003 Apr;63:273-82; Shimizu W et al. J. Am. Coll. Cardiol., 2004 Jul;44:117-25; Berge KE et al. Scand. J. Clin. Lab. Invest., 2008;68:362-8). In addition, multiple functional studies suggest this alteration leads to deficient protein function (Murray A et al. J. Med. Genet., 2002 Sep;39:681-5; Wu J et al. J. Am. Coll. Cardiol., 2014 Mar;63:819-27). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Molecular Genetics Laboratory - Cardiogenetics, CHU de Nantes	RCV000003294	SCV004024212	pathogenic	Long QT syndrome 1	2023-08-01	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000003294	SCV005399103	pathogenic	Long QT syndrome 1	2022-03-31	criteria provided, single submitter	clinical testing	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 in short QT syndrome (MIM#609621), while dominant negative and loss of function variants are associated with long QT syndrome (LQTS, MIM#192500), atrial fibrillation (MIM#607554) and Jervell and Lange-Nielsen syndrome (JLNS, MIM#220400; OMIM, PMID: 19632626, 28438721). (I) 0108 - This gene is known to be associated with both recessive and dominant disease. While this gene is mostly associated with dominant disease, JLNS is inherited as an autosomal recessive disorder (PMID: 28438721). (I) 0112 - The condition associated with this gene has incomplete penetrance (OMIM, GeneReviews). (I) 0200 - Variant is predicted to result in a missense amino acid change from glycine to serine. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v2 & v3) <0.001 for a dominant condition (1 heterozygote, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position, p.(Gly269Asp), has been observed in gnomAD (v2; 2 heterozygotes, 0 homozygotes). (I) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated S5 transmembrane domain (PMID: 29439887). (I) 0702 - Other missense variants comparable to the one identified in this case have strong previous evidence for pathogenicity. Alternative missense changes to aspartic acid, arginine, and valine are all classified as pathogenic in ClinVar. (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been described in many individuals with long QT syndrome or sudden unexplained death (ClinVar, PMID: 12702160, 15466642, 12205113, 15234419, 22677073, 29439887). (SP) 0906 - Segregation evidence for this variant is inconclusive. This variant has been reported to segregate in families with long QT syndrome, although it is also present in unaffected individuals, likely reflecting incomplete penetrance (PMID: 15176425, 12702160, 15234419, 29439887). (I) 1002 - This variant has moderate functional evidence supporting abnormal protein function. In vitro studies show that this variant has abnormal delayed rectifier potassium current, defects in subcellular localisation, reduced stability, and a dominant negative effect over wild type (PMID: 20044973, 24184248). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
OMIM	RCV000003294	SCV000023452	pathogenic	Long QT syndrome 1	2002-09-01	no assertion criteria provided	literature only
Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust	RCV000057765	SCV000089284	not provided	Congenital long QT syndrome		no assertion provided	literature only	This variant has been reported as associated with Long QT syndrome in the following publications (PMID:10560595;PMID:12205113;PMID:12702160;PMID:14678125;PMID:15466642;PMID:15840476;PMID:17905336;PMID:18752142;PMID:19716085;PMID:19808498;PMID:20044973;PMID:15234419;PMID:17470695). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.