ClinVar Genomic variation as it relates to human health

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

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). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on KCNQ1 protein function. 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.

PS4, PM1_strong, PP1_strong, PS3_mod, PM2, PM5, PP2, PP3, PP5

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 variant was reported in individual(s) with features consistent with long QT syndrome (LQTS) and segregated with disease in at least one family (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 multiple assays testing KCNQ1 function, this variant showed functionally abnormal results (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).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 variant is interpreted as a disease-causing mutation.

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.

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)

This missense variant replaces glycine with serine at codon 269 of the KCNQ1 protein. This variant is found within the highly conserved transmembrane domain S5 (a.a. 262-282). Rare non-truncating variants in this region have been shown to be significantly overrepresented in individuals with long QT syndrome (PMID: 32893267). A functional study has shown that this variant leads to a modest reduction in potassium channel current under control conditions and results in a completely blunted channel response to PKA stimulation (PMID: 24184248). This variant has been reported in at least twenty unrelated individuals affected with long QT syndrome (PMID: 12702160, 15176425, 15234419, 17905336, 24184248, 27920829, 29740400, 32893267, 38489124). It has been shown that this variant segregates with disease in four of the families (PMID: 24184248). This variant has also been reported in two individuals affected with sudden death (PMID: 16436635, 22677073) as well as in some asymptomatic individuals (PMID: 10560595, 12702160). This variant has been identified in 1/250528 chromosomes in the general population by the Genome Aggregation Database (gnomAD). A different variant affecting the same codon, c.806G>A (p.Gly269Asp), is considered to be disease-causing (ClinVar variation ID: 3145), suggesting that glycine at this position is important for the protein function. Based on the available evidence, this variant is classified as Pathogenic.

This missense variant replaces glycine with serine at codon 269 of the KCNQ1 protein. This variant is found within the highly conserved transmembrane domain S5 (a.a. 262-282). Rare non-truncating variants in this region have been shown to be significantly overrepresented in individuals with long QT syndrome (PMID: 32893267). A functional study has shown that this variant leads to a modest reduction in potassium channel current under control conditions and results in a completely blunted channel response to PKA stimulation (PMID: 24184248). This variant has been reported in at least twenty unrelated individuals affected with long QT syndrome (PMID: 12702160, 15176425, 15234419, 17905336, 24184248, 27920829, 29740400, 32893267, 38489124). It has been shown that this variant segregates with disease in four of the families (PMID: 24184248). This variant has also been reported in two individuals affected with sudden death (PMID: 16436635, 22677073) as well as in some asymptomatic individuals (PMID: 10560595, 12702160). This variant has been identified in 1/250528 chromosomes in the general population by the Genome Aggregation Database (gnomAD). A different variant affecting the same codon, c.806G>A (p.Gly269Asp), is considered to be disease-causing (ClinVar variation ID: 3145), suggesting that glycine at this position is important for the protein function. Based on the available evidence, this variant is classified as Pathogenic.

Absent from controls (or at extremely low frequency if recessive) in Genome Aggregation Database, Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium.;Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.;The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.;Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.;Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.

Assessed according to the ClinGen Potassium Channel Arrhythmia Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for KCNQ1 Version 1.0.0. Applied criteria: PS3, PS4, PP3.

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.