ClinVar Miner

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

dbSNP: rs120074193
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Total submissions: 8
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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)
Invitae 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
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.

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