ClinVar Miner

Submissions for variant NM_181798.1(KCNQ1):c.1321G>A (p.Gly441Arg) (rs199472807)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000505735 SCV000234521 pathogenic not provided 2018-06-06 criteria provided, single submitter clinical testing The G568R pathogenic variant in the KCNQ1 gene has been previously reported in multiple individuals in association with LQTS (Tester et al., 2005; Kapa et al., 2009; Kapplinger et al., 2009; Goldenberg et al., 2011; Giudicessi et al., 2012; Medlock et al., 2012; Barshshet et al., 2012; Giudicessi et al., 2013; Poterucha et al., 2015; Robinson et al., 2015). This variant has also been identified independently in multiple unrelated individuals with LQTS referred for genetic testing at GeneDx. Additionally, G568R has been shown to segregate with LQTS in multiple affected relatives from unrelated families, as reported by Giudicessi et al. (2013) and observed at GeneDx. This variant is not observed in large population cohorts (Lek et al., 2016). The G568R 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. Furthermore, in silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Finally, pathogenic/likely pathogenic missense variants at the same residue (G568A), and in nearby residues (S566Y, S566F, I567T), have been reported at GeneDx and/or in HGMD in association with LQTS (Stenson et al., 2014), supporting the functional importance of this residue and region of the protein.In summary, G568R in the KCNQ1 gene is interpreted as a pathogenic variant.
Ambry Genetics RCV000250706 SCV000320027 pathogenic Cardiovascular phenotype 2019-07-26 criteria provided, single submitter clinical testing The p.G568R pathogenic mutation (also known as c.1702G>A), located in coding exon 14 of the KCNQ1 gene, results from a G to A substitution at nucleotide position 1702. The glycine at codon 568 is replaced by arginine, an amino acid with dissimilar properties. This mutation has been reported in multiple individuals with long QT syndrome (LQTS) (Tester et al. Heart Rhythm. 2005 May;2(5):507-17; Kapplinger et al. Heart Rhythm. 2009 Sep;6(9):1297-303). In addition, this mutation was seen in a compound heterozygote with LQTS, who also harbored an in-frame deletion of the KCNQ1 gene; her mother and maternal first cousin with QT interval prolongation were heterozygous for the p.G568R alteration (Giudicessi, JR and Ackerman, MJ. Cir Cardiovasc Genet. 2013 Apr;6(2):193-200 ). Alternate amino acid substitutions, p.G568A and p.G568E, have also been reported in individuals with LQTS (Chen S et al. Clin. Genet., 2003 Apr;63:273-82; Izumi G et al. Pediatr Cardiol, 2016 Jun;37:962-70). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001192510 SCV001360699 pathogenic Long QT syndrome 2021-06-13 criteria provided, single submitter clinical testing Variant summary: KCNQ1 c.1702G>A (p.Gly568Arg) results in a non-conservative amino acid change located in the C-terminal domain (IPR013821) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251094 control chromosomes. c.1702G>A has been reported in the literature in multiple individuals affected with Long QT Syndrome (example, Giudicessi_2013, Kapplinger_2009). In one of these reports this variant co-segregated with prolonged QTc interval in a family (Giudicessi_2013). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic (n=3)/likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae RCV001192510 SCV001576433 likely pathogenic Long QT syndrome 2020-09-18 criteria provided, single submitter clinical testing This sequence change replaces glycine with arginine at codon 568 of the KCNQ1 protein (p.Gly568Arg). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and arginine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in several individuals and families affected with long QT syndrome (PMID: 22949429, 22456477, 22956155, 23392653). ClinVar contains an entry for this variant (Variation ID: 53009). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: Deleterious; PolyPhen-2: Probably Damaging; Align-GVGD: Class C1). This variant disrupts the p.Gly568 amino acid residue in KCNQ1. Other variant(s) that disrupt this residue have been observed in individuals with KCNQ1-related conditions (PMID: 12702160), which suggests that this may be a clinically significant amino acid residue. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Mayo Clinic Laboratories, Mayo Clinic RCV000505735 SCV001714961 likely pathogenic not provided 2020-01-10 criteria provided, single submitter clinical testing PS4_Moderate, PM2, PM3, PP1, PP3
Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust RCV000057622 SCV000089141 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:15840476;PMID:19716085;PMID:19841300). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.
Clinical Molecular Genetics Laboratory,Johns Hopkins All Children's Hospital RCV000678815 SCV000805001 pathogenic not specified 2016-02-29 no assertion criteria provided clinical testing

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