ClinVar Miner

Submissions for variant NM_000218.3(KCNQ1):c.535G>A (p.Gly179Ser) (rs199473394)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000505781 SCV000234385 pathogenic not provided 2018-02-28 criteria provided, single submitter clinical testing The G179S pathogenic variant in the KCNQ1 gene has been reported multiple times in association with LQTS (Splawski et al., 2000; Westenskow et al., 2004; Kapplinger et al., 2009; Anderson et al., 2015; Vyas et al., 2016). Westenskow et al. (2004) reported G179S co-segregated with a LQTS phenotype in one family with multiple affected family members, including two relatives who were homozygous for this variant. The homozygous individuals were symptomtomatic and exhibited more pronounced long QT intervals compared to the heterozygous carriers, who had no symptoms and modest QT prolongation (Westenskow et al., 2004). Most recently, Vyas et al. (2016) described a patient and his sister who were homozygous for the G179S variant and exhibited symptoms of autosomal recessive Romano-Ward syndrome. This variant has also been shown to be associated with an extremely prolonged QT interval in a heterozgyous individual (Anderson et al., 2015). The G179S variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). G179S 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. This substitution occurs at a position that is conserved across species. In addition, Splawski et al. (2002) reported that G179S expressed with wild-type KCNQ1 led to a loss of function effect. Finally, missense variants in nearby residues (R174P, A178P, K183R, K183M, Y184H, Y184S) have been reported in the Human Gene Mutation Database in association with LQTS (Stenson et al., 2014), further supporting the functional importance of this region of the protein.
Institute of Medical Genetics and Genomics,Sir Ganga Ram Hospital RCV000234794 SCV000240227 pathogenic Long QT syndrome 1 2014-01-01 criteria provided, single submitter research
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000057694 SCV000711392 pathogenic Congenital long QT syndrome 2019-03-15 criteria provided, single submitter clinical testing The p.Gly179Ser variant in KCNQ1 has been reported in the heterozygous state in at least 3 individuals with autosomal dominant long QT syndrome (LQTS), one of whom had a more severe phenotype and carried a presumed pathogenic variant in another LQTS gene (Splawski 2000, Kapplinger 2009, Fernandes 2015, Natarajan 2016). It has also been reported in the homozygous or compound heterozygous state in 4 individuals with severe autosomal recessive LQTS (AR-LQTS) and segregated with AR-LQTS in 3 affected relatives from 2 families (Westenskow 2004, Giudicessi 2013, Vyas 2016, Bdier 2017). Individuals with AR-LQTS typically had a more severe phenotype with an earlier age of onset than heterozygotes, but none were reported to have hearing loss. Relatives of these individuals who were heterozygous carriers of this variant were often clinically asymptomatic or had modestly prolonged QT interval; however 1 heterozygous carrier experienced sudden cardiac death (Westenskow 2004, Giudicessi 2013, Bdier 2017), suggesting reduced penetrance and variable expressivity for the autosomal dominant form of LQTS associated with this variant. In vitro functional studies and computational prediction tools support an impact on protein function (Westenskow 2004, Huang 2018). This variant has been reported by other clinical laboratories in ClinVar (Variation ID 53063) and was absent from large population studies. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant and autosomal recessive LQTS. ACMG/AMP Criteria applied: PM3_Strong, PM2, PP1_Moderate, PP3, PS3_Supporting, PS4_Supporting.
Ambry Genetics RCV000620835 SCV000737634 pathogenic Cardiovascular phenotype 2020-01-17 criteria provided, single submitter clinical testing The p.G179S pathogenic mutation (also known as c.535G>A), located in coding exon 3 of the KCNQ1 gene, results from a G to A substitution at nucleotide position 535. The glycine at codon 179 is replaced by serine, an amino acid with similar properties. This alteration has been detected in the heterozygous, homozygous, and compound heterozygous state in numerous unrelated individuals with longQT syndrome (LQTS) (Splawski I, Circulation 2000 Sep; 102(10):1178-85; Kapplinger JD, Heart Rhythm 2009 Sep; 6(9):1297-303; Anderson HN, Pediatr Cardiol 2015 Oct; 36(7):1350-6; Fernandes M et al. Rev Port Cardiol, 2015 May;34:359.e1-5; Natarajan P et al. Sci Transl Med, 2016 11;8:364ra151; Al-Hassnan ZN et al. Heart Rhythm, 2017 08;14:1191-1199). The alteration has been reported to segregate with disease in multiple families, with homozygous and compound heterozygous individuals typically displaying more pronounced prolongation of the QT interval compared with heterozyous relatives (Westenskow P et al. Circulation, 2004 Apr;109:1834-41; Giudicessi JR et al. Circ Cardiovasc Genet, 2013 Apr;6:193-200; Vyas B et al. Am. J. Med. Genet. A, 2016 06;170:1510-9; Bdier AY et al. Mol Genet Genomic Med, 2017 Sep;5:592-601). Several functional studies indicate that this alteration results in a trafficking defect and reduced potassium current in heterologous expression systems (Westenskow P et al. Circulation, 2004 Apr;109:1834-41; Huang H et al. Sci Adv, 2018 03;4:eaar2631). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology RCV000234794 SCV001192817 pathogenic Long QT syndrome 1 2019-12-19 criteria provided, single submitter research
Color Health, Inc RCV001185984 SCV001352304 likely pathogenic Arrhythmia 2021-01-11 criteria provided, single submitter clinical testing This missense variant replaces glycine with serine at codon 179 in the cytoplasmic linker between transmembrane domains S2 and S3 of the KCNQ1 protein. Computational prediction tools and conservation analyses suggest that this variant may have deleterious impact on the protein function. Experimental functional assays have shown that this variant may cause a decreased surface expression of the potassium channel protein and a reduced channel current (PMID: 15051636 , 29532034). This variant has been reported in heterozygosity in multiple individuals affected with long QT syndrome (PMID: 15051636, 19716085, 25845942, 27831900, 28438721). This variant has been shown to segregate with long QT syndrome in 5 affected individuals from a family, with a more extreme phenotype in homozygous individuals compared to heterozygous individuals (PMID: 15051636). This variant has also been associated with autosomal recessive long QT syndrome in some families (PMID: 23392653, 27041150, 28944242, 29684900). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on available evidence, this variant is classified as Likely Pathogenic.
Invitae RCV000148544 SCV001581994 pathogenic Long QT syndrome 2020-06-04 criteria provided, single submitter clinical testing This sequence change replaces glycine with serine at codon 179 of the KCNQ1 protein (p.Gly179Ser). The glycine residue is highly conserved and there is a small physicochemical difference between glycine and serine. This variant is not present in population databases (ExAC no frequency). This variant has been observed to segregate in several families with long QT syndrome (LQTS) (PMID: 15051636, 28944242) and in individuals affected with LQTS (PMID: 10973849, 15051636, 23392653, 27041150, 27831900). ClinVar contains an entry for this variant (Variation ID: 53063). Experimental studies have shown that this missense change decreases sodium channel function (PMID: 15051636, 29532034). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. For these reasons, this variant has been classified as Pathogenic.
Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust RCV000057694 SCV000089213 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:10973849;PMID:15051636;PMID:19716085). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.
CSER _CC_NCGL, University of Washington RCV000148544 SCV000190257 likely benign Long QT syndrome 2014-06-01 no assertion criteria provided research

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