Submissions for variant NM_000218.3(KCNQ1):c.1768G>A (p.Ala590Thr)

gnomAD frequency: 0.00002  dbSNP: rs199472813

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000182224	SCV000234527	uncertain significance	not provided	2022-10-30	criteria provided, single submitter	clinical testing	Reported in association with sinus bradycardia and LQTS or suspected LQTS (Lupoglazoff et al., 2004; Tester et al., 2005; Kapa et al., 2009; Ebrahim et al., 2017; Smith et al., 2017; Strand et al., 2020); of note, one of the probands with a prolonged QTc was homozygous for this variant and had normal hearing (Smith et al., 2017); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 19841300, 34505893, 31565860, 32421437, 17329209, 15840476, 22949429, 17329207, 18174212, 19825999, 19322600, 16623272, 28491806, 28532774, 24713462, 32048431, 31589614, 14998624)
CeGaT Center for Human Genetics Tuebingen	RCV000182224	SCV001148160	likely pathogenic	not provided	2021-01-01	criteria provided, single submitter	clinical testing
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	RCV001027732	SCV001190323	likely pathogenic	Long QT syndrome 1	2019-11-15	criteria provided, single submitter	research
Color Diagnostics, LLC DBA Color Health	RCV001841637	SCV001352303	likely pathogenic	Cardiac arrhythmia	2023-08-14	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with threonine at codon 590 of the KCNQ1 protein. This variant is found within a highly conserved region (a.a.585-607) of C-terminal cytoplasmic coiled-coil domain. Rare nontruncating variants in this region have been shown to be significantly overrepresented in individuals with long QT syndrome (PMID: 32893267). A functional study has shown that this variant may adversely affect channel trafficking to the cell surface and function (PMID: 24713462). This variant has been reported in about ten unrelated individuals affected with long QT syndrome which was congenital in half of the probands (PMID: 14998624, 15840476, 16623272, 19841300, 23130128, 24713462, 28491806, 28532774, 32421437, 34395343). The variant has been observed in homozygous state in one of these individuals, who was from a consanguineous family and showed severe phenotypes but no hearing loss (PMID: 28491806). Both parents and two siblings were unaffected heterozygous and a distant cousin had sudden death at young age also in the setting of consanguinity. This variant has been identified in 3/282306 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001852971	SCV002143565	pathogenic	Long QT syndrome	2024-01-11	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 590 of the KCNQ1 protein (p.Ala590Thr). This variant is present in population databases (rs199472813, gnomAD 0.004%). This missense change has been observed in individuals with definite or suspected long QT syndrome (PMID: 14998624, 22949429, 23130128, 24713462, 28491806). ClinVar contains an entry for this variant (Variation ID: 53015). 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) performed at Invitae indicates that this missense variant is expected to disrupt KCNQ1 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects KCNQ1 function (PMID: 24713462). For these reasons, this variant has been classified as Pathogenic.
Center For Human Genetics And Laboratory Diagnostics, Dr. Klein, Dr. Rost And Colleagues	RCV001027732	SCV002320713	likely pathogenic	Long QT syndrome 1	2022-01-13	criteria provided, single submitter	clinical testing
Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust	RCV000057634	SCV000089153	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:14998624;PMID:15840476;PMID:16623272;PMID:17329209;PMID:19841300;PMID:17329207). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000223805	SCV000280150	uncertain significance	not specified	2013-11-13	no assertion criteria provided	clinical testing	Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. KCNQ1 p.Ala590Thr Based on the data reviewed below we consider it a variant of uncertain significance, likely disease causing. The variant has been seen in one case of long QT, another case of possible neonatal long QT, and one case of drug-induced long QT. There is no segregation data available. Lupoglazoff et al (2004) first reported this variant in their French cohort. They observed it in a neonate with long QT syndrome. The patient was a male who presented with neonatal bradycardia and a QTc of 460 ms. At follow-up at 6 years of age he was asymptomatic. They note that the variant was inherited from the mother but no phenotypic data on the mother is provided. I had our peds EP team review this case and they felt the data reported was perhaps suspicious for a diagnosis of long QT but did not strongly support it. Couderc et al (2012) included a patient with this variant in an analysis of QT-RR relationship in patients with long QT, however the data for that study was pulled from a French database so this may be the same case that was reported by Lupoglazoff et all (2004). The variant was also reported in a compendium of variants found in Dr. Ackerman's research lab (Tester et al 2005). The variant was observed in 1 of 541 individuals with "suspected" long QT syndrome enrolled in Dr. Ackerman's studies. Individual phenotypic data was not reported, however sufficient data was available to calculate a Schwartz score in 77% of cases. A Schwartz score ? 4 (indicating high confidence in the diagnosis) was present 29% of the overall cohort and 40% of individuals with a KCNQ1 variant. The overall yield was 50%, compared to 70% in studies where all the patients had a firmer diagnosis of long QT syndrome. Taken together these data suggest that a proportion of patients in this study did not in fact have long QT syndrome. However, the same group later included a case with this variant in two other publications and noted that only cases with a strong diagnosis (Schwartz score ? 4 or QTc ? 480 ms were included) (Kapa et al 2009, Giudicessi et al 2012). Given ascertainment methods for the three papers it is likely they are all referring to the same case. I suspect this case was also included in a paper by Goldenberg et al (2011) and one by Barsheshet et al (2012) as Dr. Ackerman is a co-author on both and cases from his cohort were included. Goldenberg et al (2011) list three individuals with p.Ala590Thr, however the study included people with long QT and genotype-positive, phenotype-negative relatives, and it is unclear whether those three individuals had phenotype. Novotny et al (2006) reported the variant in a study on drug-induced long QT, though unfortunately the paper is in Czech. Using google translate it looks like they observed the variant in male with a QTc of 450 ms while on venlafixine (Effexor). In silico analysis with PolyPhen-2 predicts the variant to be possibly damaging. The alanine at codon 590 is conserved across mammals but is a serine in fugu and c elegans. Other variants have been reported in association with disease at nearby codons (p.Thr587Met, p.Gly589Asp, p.Arg591Cys, p.Arg591His, p.Arg594Gln, p.Arg594Pro, p.Glu596Lys). In total the variant has not been seen in ~8100 published controls and individuals from publicly available population datasets. There is no variation at codon 590 listed in the NHLBI Exome Sequencing Project dataset, which currently includes variant calls on 6500 Caucasian and African American individuals (as of February 27th, 2013). The variant is in 1000 genomes and dbSNP (rs199472813) but only in reference to the reports with long QT syndrome.The variant was not observed in the following published control samples: 100 reportedly healthy individuals analyzed by Lupoglazoff et al (2004), 1500 presumed healthy individuals analyzed by Kapa et al (2009).