ClinVar Miner

Submissions for variant NM_181798.1(KCNQ1):c.971G>A (p.Arg324Gln) (rs199472781)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000057581 SCV000234490 uncertain significance not provided 2018-10-24 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the KCNQ1 gene. The R451Q variant has been previously reported in one Japanese individual in association with LQTS (Shimizu et al., 2004), and has been observed in one other individual referred for LQTS genetic testing at GeneDx. However, no segregation data was available for either of these individuals. Additionally, R451Q was found in one African American individual from a cohort of ostensibly healthy control individuals (Ackerman et al., 2003; Kapa et al., 2009; Giudicessi et al., 2012), although a follow-up cardiac evaluation was not reported. Nevertheless, the R451Q variant was not observed with any significant frequency in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Furthermore, R451Q is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved in mammals, however, Glutamine is tolerated at this position in at least one mammalian species, and in silico analysis predicts this variant likely does not alter the protein structure/function. Finally, a missense variant at the same residue (R451W) has been reported in HGMD in association with LQTS (Stenson et al., 2014), however, the clinical significance of this variant has not been definitely determined. Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign.
Color Health, Inc RCV000777932 SCV000914029 uncertain significance Arrhythmia 2020-08-09 criteria provided, single submitter clinical testing This missense variant replaces arginine with glutamine at codon 451 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 reported for this variant. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 13/281216 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The relatively high frequency of this variant in the general population suggests that this variant is unlikely to be disease-causing. However, additional studies are necessary to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Illumina Clinical Services Laboratory,Illumina RCV001104620 SCV001261498 benign Short QT syndrome 2 2017-04-27 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign.
Illumina Clinical Services Laboratory,Illumina RCV001104828 SCV001261721 uncertain significance Long QT syndrome 1 2017-04-27 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Clinical Services Laboratory,Illumina RCV001104829 SCV001261722 uncertain significance Atrial fibrillation, familial, 3 2017-04-27 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Clinical Services Laboratory,Illumina RCV001104830 SCV001261723 uncertain significance Jervell and Lange-Nielsen syndrome 1 2017-04-27 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Invitae RCV000148550 SCV001401523 uncertain significance Long QT syndrome 2020-01-18 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 451 of the KCNQ1 protein (p.Arg451Gln). The arginine residue is moderately conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs199472781, ExAC 0.04%). This variant has been reported in an individual affected with long QT syndrome (PMID: 15234419) and in a control individual (PMID: 22949429). ClinVar contains an entry for this variant (Variation ID: 67029). This variant identified in the KCNQ1 gene is located in the cytoplasmic C-terminal region of the resulting protein (PMID: 19841300, 25348405), but 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 output the following: SIFT: Deleterious; PolyPhen-2: Benign; Align-GVGD: Class C0. The glutamine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. 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.
Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust RCV000057581 SCV000089100 not provided not provided no assertion provided literature only This variant has been reported in the following publications (PMID:14661677;PMID:15234419;PMID:19841300;PMID:22378279).
CSER _CC_NCGL, University of Washington RCV000148550 SCV000190263 uncertain significance Long QT syndrome 2014-06-01 no assertion criteria provided research

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