ClinVar Miner

Submissions for variant NM_181798.1(KCNQ1):c.1450G>A (p.Asp484Asn) (rs147445322)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Biesecker Lab/Clinical Genomics Section,National Institutes of Health RCV000148559 SCV000055218 likely benign Long QT syndrome 2013-06-24 criteria provided, single submitter research
GeneDx RCV000182235 SCV000234538 uncertain significance not provided 2018-05-02 criteria provided, single submitter clinical testing The D611N variant of uncertain significance in the KCNQ1 gene has been reported multiple times in association with LQTS, although specific clinical information for patients harboring this variant was not provided (Kapplinger et al., 2009; Andrsova et al., 2012; Coto et al., 2017). A more recent study found that an individual carrying a heterozygous D611N variant had a mean QTc interval that was not significantly different than the mean QTc interval observed in approximately 6,000 Danish control subjects (Ghouse et al., 2015). This variant is observed in 10/86082 (0.01%) alleles from individuals of European (non-Finnish) ancestry in large population cohorts (Lek et al., 2016). In-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function. Nevertheless, the D611N variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties.
Invitae RCV000148559 SCV000543286 uncertain significance Long QT syndrome 2018-10-08 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with asparagine at codon 611 of the KCNQ1 protein (p.Asp611Asn). The aspartic acid residue is weakly conserved and there is a small physicochemical difference between aspartic acid and asparagine. This variant is present in population databases (rs147445322, ExAC 0.2%). This variant has been reported in the literature in one individual affected with long QT syndrome (LQTS) (PMID: 22727609) and in one individual with suspected LQTS (PMID: 19716085). However it has also been reported in unaffected individuals (PMID: 23861362) and in a random sample of individuals where variant carriers did not show a significant difference in QT interval compared to non-carriers (PMID: 26159999). ClinVar contains an entry for this variant (Variation ID: 67059). This variant identified in the KCNQ1 gene is located in the cytoplasmic subunits assembly region of the resulting protein (PMID: 19841300). For more information about the location of this variant, please visit It is unclear how this variant impacts the function of this protein. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies. In summary, this variant is a rare missense change that is not predicted to affect protein function. It has been reported in both the population and affected individuals, but the available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne RCV000755676 SCV000883084 likely pathogenic Long QT syndrome 1 2018-11-21 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000825351 SCV000966646 uncertain significance not specified 2018-02-10 criteria provided, single submitter clinical testing The p.Asp611Asn variant in KCNQ1 has been reported in 3 individuals with Long QT syndrome (Andrsova 2012, Hedley 2009, Kapplinger 2009). It was also identified in 1 child with congenital profound hearing loss and a borderline QTc of 446 ms ec who had a second VUS in KCNQ1 in trans. The variant was found in the heterozy gous state in the child's unaffected mother (Wang 2017). In another study this variant was found in a heterozygous individual whose mean QTc interval was not s tatistically different than the mean QTc interval observed in 6061 Danish contro l individuals that were negative for the variant (Ghouse 2015). This variant ha s been identified in several populations by the Genome Aggregation Database with the highest allele frequency of 10/86082 European chromosomes (gnomAD, http://g; dbSNP rs147445322) and is reported in ClinVar (Variat ion ID: 67059) by several laboratories or studies. Although the variant has been seen in unaffected individuals and in the general population, we cannot rule ou t a causative role due to reduced penetrance and variable expressivity that has been noted in some long QT families. Computational prediction tools and conserva tion analysis do not provide strong support for or against an impact to the prot ein. In summary, due its presence in both affected and unaffected individuals, l imited familial segregation data, and its frequency in the general population, t he clinical significance of the p.Asp611Asn variant is uncertain. ACMG/AMP Crite ria applied: None.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000182235 SCV001334977 uncertain significance not provided 2020-02-01 criteria provided, single submitter clinical testing
Color RCV001190869 SCV001358495 uncertain significance Arrhythmia 2019-11-19 criteria provided, single submitter clinical testing
Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust RCV000057643 SCV000089162 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:19716085;PMID:19862833;PMID:22378279). 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 RCV000148559 SCV000190272 uncertain significance Long QT syndrome 2014-06-01 no assertion criteria provided research

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