Submissions for variant NM_000218.3(KCNQ1):c.1831G>A (p.Asp611Asn)

gnomAD frequency: 0.00007  dbSNP: rs147445322

Total submissions: 11

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	2022-09-21	criteria provided, single submitter	clinical testing	Reported multiple times in association with LQTS or sudden cardiac arrest, though many publications lack patient-specific data (Kapplinger et al., 2009; Andrsova et al., 2012; Illikova et al., 2015; Coto et al., 2017; Kwok et al., 2018; Giudicessi et al, 2018); Reported in a Danish cohort screened for LQTS variants where QTc intervals in carriers were not statistically different compared with non-carriers (Ghouse et al., 2015); Reported in a 6-year-old Chinese proband with congential profound deafness and QTc of 446. He also harbored a second missense variant in trans in the KCNQ1 gene. The p.(D611N) variant was inherited from his mother with normal hearing and a normal QTc interval (Wang et al., 2017).; In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 25637381, 22727609, 23861362, 28749187, 22378279, 19862833, 25554238, 26159999, 29197658, 26633542, 25854863, 30530868, 29884292, 31019283, 32048431, 33614747, 27917693, 19716085)
Invitae	RCV000148559	SCV000543286	uncertain significance	Long QT syndrome	2024-01-30	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 611 of the KCNQ1 protein (p.Asp611Asn). This variant is present in population databases (rs147445322, gnomAD 0.01%). This missense change has been observed in individual(s) with clinical features of Jervell and Lang-Nielsen syndrome and/or clinical features of long QT syndrome (PMID: 19716085, 22727609, 25554238, 27917693, 30530868). ClinVar contains an entry for this variant (Variation ID: 67059). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on KCNQ1 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant 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, Mass General Brigham 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 nomad.broadinstitute.org/; 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.
Color Diagnostics, LLC DBA Color Health	RCV001841678	SCV001358495	uncertain significance	Cardiac arrhythmia	2023-05-01	criteria provided, single submitter	clinical testing	This missense variant replaces aspartic acid with asparagine at codon 611 of the KCNQ1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been performed for this variant. This variant has been reported in two individuals affected with long QT syndrome (PMID: 22727609, 33614747), in an individual suspected to be affected with long QT syndrome (PMID: 19716085), and in an individual suspected of having Jervell and Lange-Nielsen Syndrome (27917693). It has also been reported in individuals without diagnoses of KCNQ1-related disorders (PMID: 23861362, 26159999, 27917693). This variant has been identified in 17/212554 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.
Revvity Omics, Revvity	RCV000182235	SCV003811973	uncertain significance	not provided	2023-10-20	criteria provided, single submitter	clinical testing
Dept of Medical Biology, Uskudar University	RCV000148559	SCV004021965	uncertain significance	Long QT syndrome	2024-01-08	criteria provided, single submitter	research	Criteria: PM2, PM5
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000825351	SCV004030096	uncertain significance	not specified	2023-07-21	criteria provided, single submitter	clinical testing	Variant summary: KCNQ1 c.1831G>A (p.Asp611Asn) results in a conservative amino acid change located in the Potassium channel, voltage dependent, KCNQ, C-terminal (IPR013821) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 7.2e-05 in 181208 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in KCNQ1 causing Long QT Syndrome (7.2e-05 vs 0.0001), allowing no conclusion about variant significance. c.1831G>A has been reported in the literature in individuals affected with Long QT Syndrome or related phenotypes (Kapplinger_2009, Thauvin-Robinet_2019, Andrsova_2012, Tse_2021, Kwok_2018, Illikova_2015), although one publication found no significant difference in electrocardiogram results between a carrier and non-carriers of the variant (Ghouse_2015). These reports do not provide unequivocal conclusions about association of the variant with Long QT Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 19716085, 26159999, 27917693, 31019283, 22727609, 33614747, 30530868, 25554238). Six submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, and classified it as uncertain significance (n=5) or likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance.
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