ClinVar Miner

Submissions for variant NM_181798.1(KCNQ1):c.533G>C (p.Trp178Ser) (rs120074186)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000182130 SCV000234433 pathogenic not provided 2018-12-20 criteria provided, single submitter clinical testing The W305S pathogenic variant in the KCNQ1 gene has been reported in association with both Jervell and Lange-Nielsen syndrome type-1 (JLNS1) and LQTS (Neyroud et al., 1997; Neyroud et al., 1998; Tester et al., 2005; Jons et al., 2009; Kapplinger et al., 2009; Barsheshet et al., 2012; Crotti et al., 2012). Neyroud et al. (1997, 1998) identified W305S in the homozygous state in at least three individuals with JLNS1 from two unrelated, consanguineous families; the heterozygous parents in both families were reportedly unaffected. The W305S variant has also been identified in the heterozygous state, independent of additional cardiogenetic variants, in at least three unrelated individuals with LQTS referred for genetic testing at GeneDx. W305S is not observed at a significant frequency in large population cohorts (Lek et al., 2016). This variant results in a non-conservative amino acid substitution, and in silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Moreover, functional studies by Chouabe et al. (1997) demonstrate that W305S expressed in the homozygous state results in a complete loss of function of the potassium channel, while W305S expressed in conjunction with the wild-type channel results in reduced potassium channel current. Lastly, different pathogenic or likely pathogenic missense variants affecting the same residue (W305L) or nearby residues (A302E, A302V, W304R, W304L, G306R, V307M, V310I) have been reported in the Human Gene Mutation Database and/or at GeneDx in association with LQTS (Stenson et al., 2014), further supporting the functional importance of this residue and region of the protein. In summary, W305S in the KCNQ1 gene is interpreted as a pathogenic variant.
Ambry Genetics RCV000622153 SCV000738133 likely pathogenic Cardiovascular phenotype 2018-09-24 criteria provided, single submitter clinical testing The p.W305S variant (also known as c.914G>C), located in coding exon 6 of the KCNQ1 gene, results from a G to C substitution at nucleotide position 914. The tryptophan at codon 305 is replaced by serine, an amino acid with highly dissimilar properties, and is located in the pore region of the protein. In a study of long QT syndrome (LQTS) clinical genetic testing, this alteration was reported in one patient; however, clinical details were limited (Tester DJ et al. Heart Rhythm, 2005;2:507-17). This alteration was also detected in the homozygous state in two siblings and an unrelated proband with autosomal recessive Jervell and Lange-Nielsen syndrome (Neyroud N et al. Eur. J. Hum. Genet. 1998;6:129-33). In vitro functional analyses suggest that this variant significantly reduces potassium current, although in one study the impact was lessened when the alteration was co-expressed with wildtype KCNQ1 (Chouabe C et al. EMBO J. 1997;16:5472-9; Jons C et al. Sci Transl Med. 2011;3:76ra28). Internal structural analysis indicates that this alteration is moderately disruptive in a sensitive region and more disruptive than a nearby known pathogenic variant (Ambry internal data). Two variants in the same codon, p.W305R and p.W305L, have also been associated with LQTS (Kapplinger JD et al. Heart Rhythm. 2009;6:1297-303; Zhou H et al. Cardiol Young. 2016;26:754-63). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Invitae RCV001385529 SCV001585411 pathogenic Long QT syndrome 2018-11-06 criteria provided, single submitter clinical testing This sequence change replaces tryptophan with serine at codon 305 of the KCNQ1 protein (p.Trp305Ser). The tryptophan residue is highly conserved and there is a large physicochemical difference between tryptophan and serine. This variant is present in population databases (rs120074186, ExAC 0.002%). This variant has been observed to segregate with Jervell and Lange-Nielsen syndrome in a family (PMID: 9781056). This variant has also been observed in individuals affected with long QT syndrome, referred for long QT syndrome testing, and healthy individuals (PMID: 19490272, 21451124, 23158531, 26669661) ClinVar contains an entry for this variant (Variation ID: 3127). Experimental studies have shown that this missense change strongly reduces potassium channel function in a homozygous state, but shows a smaller effect in a heterozygous state (PMID: 9312006, 21451124, 26344792, 10090886). This variant disrupts the p.Trp305 amino acid residue in KCNQ1. Other variant(s) that disrupt this residue have been observed in affected individuals (PMID: 26344792, 22949429), suggesting that it is a clinically significant residue. As a result, variants that disrupt this residue are likely to be causative of disease. For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000003275 SCV000023433 pathogenic Jervell and Lange-Nielsen syndrome 1 1998-03-01 no assertion criteria provided literature only
Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust RCV000057796 SCV000089315 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:9781056;PMID:15840476;PMID:19716085;PMID:9312006;PMID:17999538). 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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