The Clinical Variant Analysis Tool: Analyzing the evidence supporting reported genomic variation in clinical practice.
The Clinical Variant Analysis Tool: Analyzing the evidence supporting reported genomic variation in clinical practice.
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DOI：
10.1016/j.gim.2022.03.013
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发表时间：
2022-07
影响因子：
8.8
通讯作者：
Boerkoel, Cornelius F.
中科院分区：
文献类型：
--
作者：
Chin, Hui-Lin;Gazzaz, Nour;Huynh, Stephanie;Handra, Iulia;Warnock, Lynn;Moller-Hansen, Ashley;Boerkoel, Pierre;Jacobsen, Julius O. B.;du Souich, Christele;Zhang, Nan;Shefchek, Kent;Prentice, Leah M.;Washington, Nicole;Haendel, Melissa;Armstrong, Linlea;Clarke, Lorne;Li, Wenhui Laura;Smedley, Damian;Robinson, Peter N.;Boerkoel, Cornelius F.
关键词：
无论实验室变异分类如何，基因组检测结果都需要临床医生判断变异对医疗决策的适用性。基因组变异的教学和标准化临床解释需要一种方法或工具。为了生成这样的工具，我们将因果关系的临床基因组资源框架和美国医学遗传学学院/分子病理学协会和Quest诊断实验室的变异危险性评分提炼成临床变异分析工具（CVAT）。将其应用于289份临床外显子组报告，我们将初级从业者的表现与经验丰富的医学遗传学家的表现进行了比较，并评估了报告变异的效用。CVAT使性能与经验丰富的医学遗传学家相当。总体而言，289份外显子组报告中的124份（42.9%）和382份报告中的146份（38.2%）变异支持诊断。总体而言，10.5%（1个致病性[P]或可能致病性[LP]变异和39个意义不确定的变异[VUS]）的变异在没有确定疾病关联的基因中报告; 20.2%（23例P/LP和54例VUS）存在于表型一致性不足的基因中; 7.3%（15例P/LP和13例VUS）与已知的分子致病机制相矛盾，24%（91例VUS）的致病证据不足。CVAT的实施标准化了基因组变异的临床解释，并强调了基因组变异的协作和透明报告的必要性。
Genomic test results, regardless of laboratory variant classification, require clinical practitioners to judge the applicability of a variant for medical decisions. Teaching and standardizing clinical interpretation of genomic variation calls for a methodology or tool. To generate such a tool, we distilled the Clinical Genome Resource framework of causality and the American College of Medical Genetics/Association of Molecular Pathology and Quest Diagnostic Laboratory scoring of variant deleteriousness into the Clinical Variant Analysis Tool (CVAT). Applying this to 289 clinical exome reports, we compared the performance of junior practitioners with that of experienced medical geneticists and assessed the utility of reported variants. CVAT enabled performance comparable to that of experienced medical geneticists. In total, 124 of 289 (42.9%) exome reports and 146 of 382 (38.2%) reported variants supported a diagnosis. Overall, 10.5% (1 pathogenic [P] or likely pathogenic [LP] variant and 39 variants of uncertain significance [VUS]) of variants were reported in genes without established disease association; 20.2% (23 P/LP and 54 VUS) were in genes without sufficient phenotypic concordance; 7.3% (15 P/LP and 13 VUS) conflicted with the known molecular disease mechanism; and 24% (91 VUS) had insufficient evidence for deleteriousness. Implementation of CVAT standardized clinical interpretation of genomic variation and emphasized the need for collaborative and transparent reporting of genomic variation.
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影响因子：
3.9
作者：
Rivera-Muñoz EA;Milko LV;Harrison SM;Azzariti DR;Kurtz CL;Lee K;Mester JL;Weaver MA;Currey E;Craigen W;Eng C;Funke B;Hegde M;Hershberger RE;Mao R;Steiner RD;Vincent LM;Martin CL;Plon SE;Ramos E;Rehm HL;Watson M;Berg JS
通讯作者：
Berg JS
影响因子：
14.9
作者：
Howe KL;Achuthan P;Allen J;Allen J;Alvarez-Jarreta J;Amode MR;Armean IM;Azov AG;Bennett R;Bhai J;Billis K;Boddu S;Charkhchi M;Cummins C;Da Rin Fioretto L;Davidson C;Dodiya K;El Houdaigui B;Fatima R;Gall A;Garcia Giron C;Grego T;Guijarro-Clarke C;Haggerty L;Hemrom A;Hourlier T;Izuogu OG;Juettemann T;Kaikala V;Kay M;Lavidas I;Le T;Lemos D;Gonzalez Martinez J;Marugán JC;Maurel T;McMahon AC;Mohanan S;Moore B;Muffato M;Oheh DN;Paraschas D;Parker A;Parton A;Prosovetskaia I;Sakthivel MP;Salam AIA;Schmitt BM;Schuilenburg H;Sheppard D;Steed E;Szpak M;Szuba M;Taylor K;Thormann A;Threadgold G;Walts B;Winterbottom A;Chakiachvili M;Chaubal A;De Silva N;Flint B;Frankish A;Hunt SE;IIsley GR;Langridge N;Loveland JE;Martin FJ;Mudge JM;Morales J;Perry E;Ruffier M;Tate J;Thybert D;Trevanion SJ;Cunningham F;Yates AD;Zerbino DR;Flicek P
通讯作者：
Flicek P
影响因子：
30.8
作者：
Kircher, Martin;Witten, Daniela M.;Jain, Preti;O'Roak, Brian J.;Cooper, Gregory M.;Shendure, Jay
通讯作者：
Shendure, Jay
影响因子：
9.8
作者：
Robinson, Peter N.;Ravanmehr, Vida;Smedley, Damian
通讯作者：
Smedley, Damian
影响因子：
3.9
作者：
Karbassi, Izabela;Maston, Glenn A.;Higgins, Joseph J.
通讯作者：
Higgins, Joseph J.