ClinVar Miner

Submissions for variant NM_181798.1(KCNQ1):c.154G>A (p.Gly52Ser) (rs199473394)

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Total submissions: 6
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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 2019-01-30 criteria provided, single submitter clinical testing proposed classification - variant undergoing re-assessment, contact laboratory
Ambry Genetics RCV000620835 SCV000737634 uncertain significance Cardiovascular phenotype 2016-07-08 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Rarity in general population databases (dbsnp, esp, 1000 genomes),In silico models in agreement (deleterious) and/or completely conserved position in appropriate species,Structural Evidence,Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation
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 Medical Center RCV000148544 SCV000190257 likely benign Long QT syndrome 2014-06-01 no assertion criteria provided research

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