ClinVar Miner

Submissions for variant NM_181798.1(KCNQ1):c.133G>A (p.Val45Met) (rs199472694)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000414067 SCV000490579 uncertain significance not provided 2021-07-26 criteria provided, single submitter clinical testing Reported in association with LQTS and sudden unexplained death (Kapplinger et al., 2009; Christiansen et al., 2016; Bdier 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: 29197658, 28438721, 31737537, 30919684, 19716085, 28944242, 27884173, 27159321, 26077850, 14678125, 27650965, 22581653, 31751626)
Ambry Genetics RCV000620765 SCV000735768 uncertain significance Cardiovascular phenotype 2018-07-13 criteria provided, single submitter clinical testing The p.V172M variant (also known as c.514G>A), located in coding exon 3 of the KCNQ1 gene, results from a G to A substitution at nucleotide position 514. The valine at codon 172 is replaced by methionine, an amino acid with highly similar properties. This variant has been reported in association with long QT syndrome (LQTS); however, clinical details were limited (Zareba W et al. J Cardiovasc Electrophysiol. 2003;14:1149-53; Kapplinger JD et al. Heart Rhythm. 2009;6(9):1297-303). This alteration has also been observed in cis with KCNQ1 p.R293C in the homozygous state in several Saudi individuals with LQTS but not the autosomal recessive Jervell and Lange-Nielson Syndrome (Al-Hassnan ZN et al. Heart Rhythm. 2017;14:1191-1199; Bdier AY et al. Mol Genet Genomic Med. 2017;5:592-601). In another Saudi family, this variant was detected in conjunction with both the KCNQ1 mutation c.1032G>A and the aforementioned KCNQ1 p.R293C alteration in several family members with LQTS; however, other family members with LQTS were only heterozygous for c.1032G>A (Al-Hassnan ZN et al. Heart Rhythm. 2017;14:1191-1199). This variant has been described as an incidental finding in an exome cohort, but cardiovascular history was not provided (Yavarna T et al. Hum Genet. 2015;134:967-80). Based on data from the Saudi Human Genome project, the A variant has a frequency of approximately 0.6% (51/4145, frequency calculation adjusted for consanguinity) of Saudi alleles and was detected in one homozygote without a disease phenotype (Abouelhoda M et al. Genome Biol. 2016;17:235). This amino acid position is not well conserved in available vertebrate species, and methionine is the reference amino acid in other vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited and conflicting at this time, the clinical significance of this alteration remains unclear.
Fulgent Genetics,Fulgent Genetics RCV000764971 SCV000896148 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
Invitae RCV000812759 SCV000953082 uncertain significance Long QT syndrome 2020-10-20 criteria provided, single submitter clinical testing This sequence change replaces valine with methionine at codon 172 of the KCNQ1 protein (p.Val172Met). The valine residue is highly conserved and there is a small physicochemical difference between valine and methionine. This variant is present in population databases (rs199472694, ExAC 0.03%). This variant has been reported in one individual affected with long QT syndrome (LQTS) and in an individual with unexplained death (PMID: 14678125, 27650965). This variant has also been observed as homozygous in a patient with LQTS, however a second homozygous variant (p.Arg293Cys) was also identified in the KCNQ1 gene in this patient (PMID: 28944242). ClinVar contains an entry for this variant (Variation ID: 67078). 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 methionine 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. 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.
Illumina Clinical Services Laboratory,Illumina RCV001102704 SCV001259389 uncertain significance Long QT syndrome 1 2017-05-16 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 RCV001106436 SCV001263501 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 RCV001107937 SCV001265125 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.
Illumina Clinical Services Laboratory,Illumina RCV001107938 SCV001265126 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.
Color Health, Inc RCV001179333 SCV001343973 uncertain significance Arrhythmia 2020-12-02 criteria provided, single submitter clinical testing This missense variant is located in the cytoplasmic linker between transmembrane domains S2 and S3 of the KCNQ1 protein. Computational prediction tools and conservation analyses are inconclusive regarding the impact of this variant on the protein function. To our knowledge, functional assays have not been performed for this variant. This variant has been reported in almost 20 individuals affected with long QT syndrome, most of whom are from Arab populations (PMID: 14678125, 28438721, 28944242, 29033053, 30919684). This variant has also been identified in 14/275842 chromosomes in the general population by the Genome Aggregation Database (gnomAD). In Clinvar, internal data from a clinical laboratory indicate that this variant is present in Arab populations at a frequency greater than expected for long QT syndrome, suggesting that it may be a benign variant in that population (RCV000414067.1). The available evidence is insufficient to determine the pathogenicity of this variant conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust RCV000057687 SCV000089206 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:14678125;PMID:19716085). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.

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