Submissions for variant NM_000218.3(KCNQ1):c.1336G>A (p.Asp446Asn)

gnomAD frequency: 0.00001  dbSNP: rs149089817

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000182184	SCV000234487	uncertain significance	not provided	2021-01-22	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Reported in ClinVar (ClinVar Variant ID# 200846; Landrum et al., 2016); In vitro studies of the Asp446Asn variant demonstrated that replacement of the negatively charged Aspartic acid with a neutral Asparagine at this residue inhibited protein S-nitrosylation, which the authors suggest is a regulatory mechanism for the KCNQ1 ion channel (Asada et al., 2009); This variant is associated with the following publications: (PMID: 19124472)
Color Diagnostics, LLC DBA Color Health	RCV001842871	SCV001350861	uncertain significance	Cardiac arrhythmia	2023-04-07	criteria provided, single submitter	clinical testing	This missense variant replaces aspartic acid with asparagine at codon 446 of the KCNQ1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). A functional study has shown that this variant disrupts a redox motif and inhibits S-nitrosylation of the KCNQ1 channel (PMID: 19124472). This variant has not been reported in individuals affected with cardiovascular disorders in the literature but has been observed in an unaffected individual (PMID: 25854863). This variant has been identified in 9/250462 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001852305	SCV002134622	likely benign	Long QT syndrome	2024-08-29	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002381589	SCV002691841	uncertain significance	Cardiovascular phenotype	2019-04-22	criteria provided, single submitter	clinical testing	The p.D446N variant (also known as c.1336G>A), located in coding exon 10 of the KCNQ1 gene, results from a G to A substitution at nucleotide position 1336. The aspartic acid at codon 446 is replaced by asparagine, an amino acid with highly similar properties, and is located in the C-terminal region. This variant has been reported as a control variant, and in a stillbirth cohort; however, clinical details were limited (Kapplinger JD et al. J Cardiovasc Transl Res, 2015 Apr;8:187-97; Sahlin E et al. PLoS ONE, 2019 Jan;14:e0210017). Assays from one study indicated this variant may impact S-nitrosylation of a neighboring residue; however, the physiological relevance of this finding is unclear (Asada K et al. J. Biol. Chem., 2009 Feb;284:6014-20). Another variant affecting this codon (p.D446E, c.1338C>G) has been detected in long QT syndrome genetic testing and sudden death cohorts; however, clinical details were limited Kapplinger JD et al. Heart Rhythm, 2009 Sep;6:1297-303; M&aacute;rquez MF et al. Arch Cardiol Mex;85:68-72). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Fulgent Genetics, Fulgent Genetics	RCV002485201	SCV002784111	uncertain significance	Atrial fibrillation, familial, 3; Beckwith-Wiedemann syndrome; Long QT syndrome 1; Jervell and Lange-Nielsen syndrome 1; Short QT syndrome type 2	2021-08-31	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV001852305	SCV004836417	uncertain significance	Long QT syndrome	2023-12-01	criteria provided, single submitter	clinical testing	This missense variant replaces aspartic acid with asparagine at codon 446 of the KCNQ1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). A functional study has shown that this variant disrupts a redox motif and inhibits S-nitrosylation of the KCNQ1 channel (PMID: 19124472). This variant has not been reported in individuals affected with cardiovascular disorders in the literature but has been observed in an unaffected individual (PMID: 25854863). This variant has been identified in 9/250462 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.