ClinVar Miner

Submissions for variant NM_181798.1(KCNQ1):c.425G>A (p.Gly142Asp) (rs120074194)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000046133 SCV000074146 pathogenic Long QT syndrome 2018-05-13 criteria provided, single submitter clinical testing This sequence change replaces glycine with aspartic acid at codon 269 of the KCNQ1 protein (p.Gly269Asp). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and aspartic acid. This variant is not present in population databases (rs120074194, ExAC no frequency). This variant has been reported to segregate with long QT syndrome in several families (PMID: 9386136, 12051962). It has also been observed in individuals with Jervell and Lange-Nielsen syndrome (PMID: 12051962) and in multiple unrelated individuals with long QT syndrome (PMID: 10973849, 17470695). Experimental studies have shown that this missense change decreases the activity of KCNQ1 (PMID: 9312006, 12522251). For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV000182119 SCV000234422 pathogenic not provided 2018-09-13 criteria provided, single submitter clinical testing The G269D pathogenic variant in the KCNQ1 gene has been reported in multiple individuals in association with LQTS (Donger et al., 1997; Splawski et al., 2000; Moss et al., 2007; Kapplinger et al., 2009), and has been observed in multiple individuals referred for LQTS genetic testing at GeneDx. It has also been identified in the compound heterozygous state with a nonsense variant in the KCNQ1 gene in at least one individual with JLNS (Wang et al., 2002). The G269D variant has been shown to segregate with disease in several heterozygous relatives from unrelated families, as reported by Donger et al. (1997) and Wang et al. (2002), and observed at GeneDx. Additionally, this variant is not observed in large population cohorts (Lek et al., 2016).The G269D 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. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Furthermore, G269D is located in the S5 transmembrane segment of KCNQ1 and functional studies have shown that G269D results in a loss of function of the ion channel (Chouabe et al., 1997; Chen et al., 2003). Finally, another missense variant at the same residue (G269S), and other missense variants in nearby residues (L266P, L266R, G272D, L273F, I274V), have been reported at GeneDx and/or in the Human Gene Mutation Database in association with arrhythmia (Stenson et al., 2014), supporting the functional importance of this residue and region of the protein.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000182119 SCV000884051 pathogenic not provided 2017-08-14 criteria provided, single submitter clinical testing The p.Gly269Asp variant (rs120074194) has been reported to segregate with disease in two unrelated families (Donger 1997 and Wang 2002), and was also identified in an individual with a history of near-drowning and a high clinical probability of having long QT syndrome (Choi 2004). The p.Gly269Asp variant was also identified in four out of 2,500 patients (0.16%) suspected of having long-QT syndrome (Kapplinger 2009), but is absent from general population databases such as 1000 Genomes, the Exome Variant Server (ESV), and the Genome Aggregation Database (gnomAD) browser. Functional studies demonstrate that the KCNQ1 p.Gly269Asp substitution eliminates activity of potassium channels (Chen 2003 and Chouabe 1997). Furthermore, another variant at this position (p.Gly269Ser) has been identified in individuals with long QT syndrome (Ackerman 1999, Choi 2004, Kapplinger 2009, Shimizu 2004, and Wu 2014). Based on the available evidence, the p.Gly269Asp variant is considered pathogenic.
OMIM RCV000003295 SCV000023453 pathogenic Long QT syndrome 1 1997-11-04 no assertion criteria provided literature only
Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust RCV000057766 SCV000089285 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:9386136;PMID:10973849;PMID:12051962;PMID:14678125;PMID:15466642;PMID:15840476;PMID:19716085;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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