ClinVar Miner

Submissions for variant NM_181798.1(KCNQ1):c.974G>A (p.Arg325Gln) (rs145229963)

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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000057583 SCV000234492 uncertain significance not provided 2017-11-20 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the KCNQ1 gene. The R452Q variant has not been published in association with arrhythmia, to our knowledge, however, it has been observed in at least one Caucasian individual from a ostensibly healthy control population (Kapa et al., 2009; Giudicessi et al., 2012; Kapplinger et al., 2015). It has been observed both independently, and in conjunction with additional cardiogenetic variants, in other individuals referred for LQTS genetic testing at GeneDx, although no informative segregation data are available to further clarify the role of this variant in disease. The R452Q variant is also observed in 23/126020 (0.02%) 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. Additionally, although a missense variant at the same residue (R452W) has been reported in association with LQTS (Tester et al., 2005), the clinical significance of this variant remains to be definitively determined.
Ambry Genetics RCV000246256 SCV000320292 uncertain significance Cardiovascular phenotype 2017-06-14 criteria provided, single submitter clinical testing The p.R452Q variant (also known as c.1355G>A), located in coding exon 10 of the KCNQ1 gene, results from a G to A substitution at nucleotide position 1355. The arginine at codon 452 is replaced by glutamine, an amino acid with highly similar properties, and is located in the C-terminal region of the protein. This alteration was reported in a long QT syndrome control cohort, but was not detected in affected individuals (Kapa S et al. Circulation. 2009;120(18):1752-60). Another alteration affecting this amino acid p.R452W (c.1354C>T), has been reported in association with long QT syndrome (Tester DJ et al. Heart Rhythm. 2005;2(5):507-17). This amino acid position is well conserved on limited sequence alignment. 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.
Illumina Clinical Services Laboratory,Illumina RCV000284895 SCV000370296 uncertain significance Congenital long QT syndrome 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000337547 SCV000370297 uncertain significance Familial atrial fibrillation 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000398200 SCV000370298 uncertain significance short QT syndrome 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000297971 SCV000370299 uncertain significance Long QT syndrome 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000355198 SCV000370300 uncertain significance Jervell and Lange-Nielsen syndrome 2016-06-14 criteria provided, single submitter clinical testing
Invitae RCV000297971 SCV000543296 uncertain significance Long QT syndrome 2020-10-12 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 452 of the KCNQ1 protein (p.Arg452Gln). The arginine residue is weakly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs145229963, ExAC 0.01%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has not been reported in the literature in individuals with KCNQ1-related disease. ClinVar contains an entry for this variant (Variation ID: 67030). 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 and their clinical significance is uncertain. 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.
Fulgent Genetics,Fulgent Genetics RCV000764975 SCV000896152 uncertain significance Atrial fibrillation, familial, 3; Beckwith-Wiedemann syndrome; Long QT syndrome 1; Jervell and Lange-Nielsen syndrome 1; Short QT syndrome 2 2018-10-31 criteria provided, single submitter clinical testing
Color Health, Inc RCV000777767 SCV000913736 uncertain significance Arrhythmia 2020-09-10 criteria provided, single submitter clinical testing This missense variant replaces arginine with glutamine at codon 452 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). To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 31/281090 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001255594 SCV001432100 uncertain significance not specified 2020-08-17 criteria provided, single submitter clinical testing Variant summary: KCNQ1 c.1355G>A (p.Arg452Gln) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00011 in 283970 control chromosomes (gnomAD and publication data). The observed variant frequency is approximately 1.1 fold of the estimated maximal expected allele frequency for a pathogenic variant in KCNQ1 causing Arrhythmia phenotype (0.0001), strongly suggesting that the variant is benign. c.1355G>A has been reported in the literature in individuals affected with Arrhythmia and long QT syndrome type 1 as well as in healthy controls (Kapa_2009, Ruwald_2016, Clemens_2018, Li_2019). These reports do not provide unequivocal conclusions about association of the variant with Arrhythmia. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust RCV000057583 SCV000089102 not provided not provided no assertion provided literature only This variant has been reported in the following publications (PMID:19841300).

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