ClinVar Miner

Submissions for variant NM_000218.3(KCNQ1):c.1903G>A (p.Gly635Arg) (rs199473484)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000767093 SCV000234539 uncertain significance not provided 2019-01-14 criteria provided, single submitter clinical testing The G635R variant of uncertain significance in the KCNQ1 gene has been reported in two individuals with LQTS and one individual with HCM (Kapplinger et al., 2009; Lopes et al., 2015), however additional clinical information was not included. The G635R variant was not observed in approximately 6,400 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The G635R variant results in a non-conservative amino acid substitution which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. However, it occurs at a position that is not well conserved across species and in silico analysis predicts that G635R likely does not alter the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000182236 SCV000539463 uncertain significance not specified 2016-10-20 criteria provided, single submitter clinical testing Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Only reported in 2-3 probands with LQT, variant aa present in other mammals
Illumina Clinical Services Laboratory,Illumina RCV001108386 SCV001265615 uncertain significance Long QT syndrome 1 2017-04-28 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 RCV001108387 SCV001265616 uncertain significance Short QT syndrome 2 2017-04-28 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 RCV001108388 SCV001265617 uncertain significance Jervell and Lange-Nielsen syndrome 1 2017-04-28 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 RCV001108389 SCV001265618 uncertain significance Atrial fibrillation, familial, 3 2017-04-28 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 RCV001188434 SCV001355493 uncertain significance Arrhythmia 2020-10-27 criteria provided, single submitter clinical testing This missense variant replaces glycine with arginine at codon 635 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 been reported in two unrelated individuals referred for long QT syndrome genetic test (PMID: 19716085) and in an individual affected with hypertrophic cardiomyopathy (PMID: 25351510). This variant has been identified in 4/222516 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.
Invitae RCV001238350 SCV001411155 uncertain significance Long QT syndrome 2019-10-16 criteria provided, single submitter clinical testing This sequence change replaces glycine with arginine at codon 635 of the KCNQ1 protein (p.Gly635Arg). The glycine residue is weakly conserved and there is a moderate physicochemical difference between glycine and arginine. This variant is present in population databases (rs199473484, ExAC 0.02%). This variant has been observed in individuals referred for long QT testing (PMID: 19716085). ClinVar contains an entry for this variant (Variation ID: 67062). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The arginine 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 RCV000057649 SCV000089168 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). 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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