Afin d’établir la causalité d’une variante génétique par rapport à un phénotype, il est nécessaire d’obtenir des preuves scientifiques suffisantes. La classification de pathogénicité proposée par l'ACMG établit 5 catégories de classification : bénin, probablement bénin, variant de signification incertaine, probablement pathogène et pathogène. Ces catégories sont définies en fonction de la probabilité qu'il existe une relation causale entre le variant détecté et le phénotype, de telle sorte qu'un variant classé comme probablement pathogène a une certitude de 90 % d'être pathogène, et un variant classé comme pathogène a une probabilité de 99 % d'être réellement pathogène. Cela signifie également que classer une variante comme VSI signifie que la probabilité que la variante soit pathogène se situe entre 11 et 89 % de probabilité.
Il a également proposé un système d'analyse des différents types de preuves, à partir de données obtenues dans des études de population, de données issues d'analyses fonctionnelles, de prédiction in silico ou d'études de ségrégation, et les a classés selon le poids relatif de chaque type de données dans l'attribution de causalité (preuve très forte, forte, modérée, favorable ou insuffisante en elle-même).
Il existe plusieurs bases de données dans lesquelles le pouvoir pathogène des variants identifiés lors d'une étude de séquençage peut être consulté, s'ils ont été préalablement décrits dans la littérature et si des investigations de causalité ont été réalisées. ClinGen est la base de données approuvée par la FDA à cet effet.
Dans le cas où les variantes n’ont pas été étudiées auparavant, il sera nécessaire d’examiner les bases de données de population, tant sur les personnes en bonne santé que sur les variantes pathogènes, ainsi que d’autres types de preuves. Varsome est un outil Web qui utilise plusieurs bases de données (dont ClinGen) pour fournir une interprétation automatisée selon les critères de l'ACMG.
19955111
{19955111:PDLBZKV3},{19955111:4WNH6ZZ4}
1
Vancouver
50
défaut
231
https://neuropediatoolkit.org/wp-content/plugins/zotpress/
%7B%22status%22%3A%22success%22%2C%22updateneeded%22%3Afalse%2C%22instance%22%3Afalse%2C%22meta%22%3A%7B%22request_last%22%3A0%2C%22request_next%22%3A0%2C%22used_cache%22%3Atrue%7D%2C%22data%22%3A%5B%7B%22key%22%3A%22PDLBZKV3%22%2C%22library%22%3A%7B%22id%22%3A19955111%7D%2C%22meta%22%3A%7B%22creatorSummary%22%3A%22MacArthur%20et%20al.%22%2C%22parsedDate%22%3A%222014%22%2C%22numChildren%22%3A1%7D%2C%22bib%22%3A%22%26lt%3Bdiv%20class%3D%26quot%3Bcsl-bib-body%26quot%3B%20style%3D%26quot%3Bline-height%3A%201.35%3B%20%26quot%3B%26gt%3B%5Cn%20%20%26lt%3Bdiv%20class%3D%26quot%3Bcsl-entry%26quot%3B%20style%3D%26quot%3Bclear%3A%20left%3B%20%26quot%3B%26gt%3B%5Cn%20%20%20%20%26lt%3Bdiv%20class%3D%26quot%3Bcsl-left-margin%26quot%3B%20style%3D%26quot%3Bfloat%3A%20left%3B%20padding-right%3A%200.5em%3B%20text-align%3A%20right%3B%20width%3A%201em%3B%26quot%3B%26gt%3B1.%26lt%3B%5C%2Fdiv%26gt%3B%26lt%3Bdiv%20class%3D%26quot%3Bcsl-right-inline%26quot%3B%20style%3D%26quot%3Bmargin%3A%200%20.4em%200%201.5em%3B%26quot%3B%26gt%3BMacArthur%20DG%2C%20Manolio%20TA%2C%20Dimmock%20DP%2C%20Rehm%20HL%2C%20Shendure%20J%2C%20Abecasis%20GR%2C%20et%20al.%20Guidelines%20for%20investigating%20causality%20of%20sequence%20variants%20in%20human%20disease.%20Nature%20%5BInternet%5D.%202014%20Abril%20%5Bcited%202015%20June%2023%5D%3B508%287497%29%3A469%26%23x2013%3B76.%20Available%20from%3A%20%26lt%3Ba%20class%3D%26%23039%3Bzp-ItemURL%26%23039%3B%20href%3D%26%23039%3Bhttp%3A%5C%2F%5C%2Fwww.nature.com%5C%2Fnature%5C%2Fjournal%5C%2Fv508%5C%2Fn7497%5C%2Ffull%5C%2Fnature13127.html%26%23039%3B%26gt%3Bhttp%3A%5C%2F%5C%2Fwww.nature.com%5C%2Fnature%5C%2Fjournal%5C%2Fv508%5C%2Fn7497%5C%2Ffull%5C%2Fnature13127.html%26lt%3B%5C%2Fa%26gt%3B%26lt%3B%5C%2Fdiv%26gt%3B%5Cn%20%20%26lt%3B%5C%2Fdiv%26gt%3B%5Cn%26lt%3B%5C%2Fdiv%26gt%3B%22%2C%22data%22%3A%7B%22itemType%22%3A%22journalArticle%22%2C%22title%22%3A%22Guidelines%20for%20investigating%20causality%20of%20sequence%20variants%20in%20human%20disease%22%2C%22creators%22%3A%5B%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22D.%20G.%22%2C%22lastName%22%3A%22MacArthur%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22T.%20A.%22%2C%22lastName%22%3A%22Manolio%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22D.%20P.%22%2C%22lastName%22%3A%22Dimmock%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22H.%20L.%22%2C%22lastName%22%3A%22Rehm%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22J.%22%2C%22lastName%22%3A%22Shendure%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22G.%20R.%22%2C%22lastName%22%3A%22Abecasis%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22D.%20R.%22%2C%22lastName%22%3A%22Adams%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22R.%20B.%22%2C%22lastName%22%3A%22Altman%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22S.%20E.%22%2C%22lastName%22%3A%22Antonarakis%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22E.%20A.%22%2C%22lastName%22%3A%22Ashley%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22J.%20C.%22%2C%22lastName%22%3A%22Barrett%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22L.%20G.%22%2C%22lastName%22%3A%22Biesecker%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22D.%20F.%22%2C%22lastName%22%3A%22Conrad%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22G.%20M.%22%2C%22lastName%22%3A%22Cooper%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22N.%20J.%22%2C%22lastName%22%3A%22Cox%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22M.%20J.%22%2C%22lastName%22%3A%22Daly%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22M.%20B.%22%2C%22lastName%22%3A%22Gerstein%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22D.%20B.%22%2C%22lastName%22%3A%22Goldstein%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22J.%20N.%22%2C%22lastName%22%3A%22Hirschhorn%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22S.%20M.%22%2C%22lastName%22%3A%22Leal%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22L.%20A.%22%2C%22lastName%22%3A%22Pennacchio%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22J.%20A.%22%2C%22lastName%22%3A%22Stamatoyannopoulos%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22S.%20R.%22%2C%22lastName%22%3A%22Sunyaev%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22D.%22%2C%22lastName%22%3A%22Valle%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22B.%20F.%22%2C%22lastName%22%3A%22Voight%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22W.%22%2C%22lastName%22%3A%22Winckler%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22C.%22%2C%22lastName%22%3A%22Gunter%22%7D%5D%2C%22abstractNote%22%3A%22The%20discovery%20of%20rare%20genetic%20variants%20is%20accelerating%2C%20and%20clear%20guidelines%20for%20distinguishing%20disease-causing%20sequence%20variants%20from%20the%20many%20potentially%20functional%20variants%20present%20in%20any%20human%20genome%20are%20urgently%20needed.%20Without%20rigorous%20standards%20we%20risk%20an%20acceleration%20of%20false-positive%20reports%20of%20causality%2C%20which%20would%20impede%20the%20translation%20of%20genomic%20research%20findings%20into%20the%20clinical%20diagnostic%20setting%20and%20hinder%20biological%20understanding%20of%20disease.%20Here%20we%20discuss%20the%20key%20challenges%20of%20assessing%20sequence%20variants%20in%20human%20disease%2C%20integrating%20both%20gene-level%20and%20variant-level%20support%20for%20causality.%20We%20propose%20guidelines%20for%20summarizing%20confidence%20in%20variant%20pathogenicity%20and%20highlight%20several%20areas%20that%20require%20further%20resource%20development.%22%2C%22date%22%3A%22Abril%2024%2C%202014%22%2C%22section%22%3A%22%22%2C%22partNumber%22%3A%22%22%2C%22partTitle%22%3A%22%22%2C%22DOI%22%3A%2210.1038%5C%2Fnature13127%22%2C%22citationKey%22%3A%22%22%2C%22url%22%3A%22http%3A%5C%2F%5C%2Fwww.nature.com%5C%2Fnature%5C%2Fjournal%5C%2Fv508%5C%2Fn7497%5C%2Ffull%5C%2Fnature13127.html%22%2C%22PMID%22%3A%22%22%2C%22PMCID%22%3A%22%22%2C%22ISSN%22%3A%220028-0836%22%2C%22language%22%3A%22en%22%2C%22collections%22%3A%5B%223W4D2W9R%22%5D%2C%22dateModified%22%3A%222026-07-15T22%3A40%3A41Z%22%7D%7D%2C%7B%22key%22%3A%224WNH6ZZ4%22%2C%22library%22%3A%7B%22id%22%3A19955111%7D%2C%22meta%22%3A%7B%22creatorSummary%22%3A%22Richards%20et%20al.%22%2C%22parsedDate%22%3A%222015-05%22%2C%22numChildren%22%3A3%7D%2C%22bib%22%3A%22%26lt%3Bdiv%20class%3D%26quot%3Bcsl-bib-body%26quot%3B%20style%3D%26quot%3Bline-height%3A%201.35%3B%20%26quot%3B%26gt%3B%5Cn%20%20%26lt%3Bdiv%20class%3D%26quot%3Bcsl-entry%26quot%3B%20style%3D%26quot%3Bclear%3A%20left%3B%20%26quot%3B%26gt%3B%5Cn%20%20%20%20%26lt%3Bdiv%20class%3D%26quot%3Bcsl-left-margin%26quot%3B%20style%3D%26quot%3Bfloat%3A%20left%3B%20padding-right%3A%200.5em%3B%20text-align%3A%20right%3B%20width%3A%201em%3B%26quot%3B%26gt%3B1.%26lt%3B%5C%2Fdiv%26gt%3B%26lt%3Bdiv%20class%3D%26quot%3Bcsl-right-inline%26quot%3B%20style%3D%26quot%3Bmargin%3A%200%20.4em%200%201.5em%3B%26quot%3B%26gt%3BRichards%20S%2C%20Aziz%20N%2C%20Bale%20S%2C%20Bick%20D%2C%20Das%20S%2C%20Gastier-Foster%20J%2C%20et%20al.%20Standards%20and%20Guidelines%20for%20the%20Interpretation%20of%20Sequence%20Variants%3A%20A%20Joint%20Consensus%20Recommendation%20of%20the%20American%20College%20of%20Medical%20Genetics%20and%20Genomics%20and%20the%20Association%20for%20Molecular%20Pathology.%20Genet%20Med%20%5BInternet%5D.%202015%20May%20%5Bcited%202016%20Sept%206%5D%3B17%285%29%3A405%26%23x2013%3B24.%20Available%20from%3A%20%26lt%3Ba%20class%3D%26%23039%3Bzp-ItemURL%26%23039%3B%20href%3D%26%23039%3Bhttp%3A%5C%2F%5C%2Fwww.ncbi.nlm.nih.gov%5C%2Fpmc%5C%2Farticles%5C%2FPMC4544753%5C%2F%26%23039%3B%26gt%3Bhttp%3A%5C%2F%5C%2Fwww.ncbi.nlm.nih.gov%5C%2Fpmc%5C%2Farticles%5C%2FPMC4544753%5C%2F%26lt%3B%5C%2Fa%26gt%3B%26lt%3B%5C%2Fdiv%26gt%3B%5Cn%20%20%26lt%3B%5C%2Fdiv%26gt%3B%5Cn%26lt%3B%5C%2Fdiv%26gt%3B%22%2C%22data%22%3A%7B%22itemType%22%3A%22journalArticle%22%2C%22title%22%3A%22Standards%20and%20Guidelines%20for%20the%20Interpretation%20of%20Sequence%20Variants%3A%20A%20Joint%20Consensus%20Recommendation%20of%20the%20American%20College%20of%20Medical%20Genetics%20and%20Genomics%20and%20the%20Association%20for%20Molecular%20Pathology%22%2C%22creators%22%3A%5B%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Sue%22%2C%22lastName%22%3A%22Richards%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Nazneen%22%2C%22lastName%22%3A%22Aziz%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Sherri%22%2C%22lastName%22%3A%22Bale%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22David%22%2C%22lastName%22%3A%22Bick%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Soma%22%2C%22lastName%22%3A%22Das%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Julie%22%2C%22lastName%22%3A%22Gastier-Foster%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Wayne%20W.%22%2C%22lastName%22%3A%22Grody%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Madhuri%22%2C%22lastName%22%3A%22Hegde%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Elaine%22%2C%22lastName%22%3A%22Lyon%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Elaine%22%2C%22lastName%22%3A%22Spector%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Karl%22%2C%22lastName%22%3A%22Voelkerding%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Heidi%20L.%22%2C%22lastName%22%3A%22Rehm%22%7D%5D%2C%22abstractNote%22%3A%22The%20American%20College%20of%20Medical%20Genetics%20and%20Genomics%20%28ACMG%29%20previously%20developed%20guidance%20for%20the%20interpretation%20of%20sequence%20variants.%20In%20the%20past%20decade%2C%20sequencing%20technology%20has%20evolved%20rapidly%20with%20the%20advent%20of%20high-throughput%20next%20generation%20sequencing.%20By%20adopting%20and%20leveraging%20next%20generation%20sequencing%2C%20clinical%20laboratories%20are%20now%20performing%20an%20ever%20increasing%20catalogue%20of%20genetic%20testing%20spanning%20genotyping%2C%20single%20genes%2C%20gene%20panels%2C%20exomes%2C%20genomes%2C%20transcriptomes%20and%20epigenetic%20assays%20for%20genetic%20disorders.%20By%20virtue%20of%20increased%20complexity%2C%20this%20paradigm%20shift%20in%20genetic%20testing%20has%20been%20accompanied%20by%20new%20challenges%20in%20sequence%20interpretation.%20In%20this%20context%2C%20the%20ACMG%20convened%20a%20workgroup%20in%202013%20comprised%20of%20representatives%20from%20the%20ACMG%2C%20the%20Association%20for%20Molecular%20Pathology%20%28AMP%29%20and%20the%20College%20of%20American%20Pathologists%20%28CAP%29%20to%20revisit%20and%20revise%20the%20standards%20and%20guidelines%20for%20the%20interpretation%20of%20sequence%20variants.%20The%20group%20consisted%20of%20clinical%20laboratory%20directors%20and%20clinicians.%20This%20report%20represents%20expert%20opinion%20of%20the%20workgroup%20with%20input%20from%20ACMG%2C%20AMP%20and%20CAP%20stakeholders.%20These%20recommendations%20primarily%20apply%20to%20the%20breadth%20of%20genetic%20tests%20used%20in%20clinical%20laboratories%20including%20genotyping%2C%20single%20genes%2C%20panels%2C%20exomes%20and%20genomes.%20This%20report%20recommends%20the%20use%20of%20specific%20standard%20terminology%3A%20%5Cu2018pathogenic%5Cu2019%2C%20%5Cu2018likely%20pathogenic%5Cu2019%2C%20%5Cu2018uncertain%20significance%5Cu2019%2C%20%5Cu2018likely%20benign%5Cu2019%2C%20and%20%5Cu2018benign%5Cu2019%20to%20describe%20variants%20identified%20in%20Mendelian%20disorders.%20Moreover%2C%20this%20recommendation%20describes%20a%20process%20for%20classification%20of%20variants%20into%20these%20five%20categories%20based%20on%20criteria%20using%20typical%20types%20of%20variant%20evidence%20%28e.g.%20population%20data%2C%20computational%20data%2C%20functional%20data%2C%20segregation%20data%2C%20etc.%29.%20Because%20of%20the%20increased%20complexity%20of%20analysis%20and%20interpretation%20of%20clinical%20genetic%20testing%20described%20in%20this%20report%2C%20the%20ACMG%20strongly%20recommends%20that%20clinical%20molecular%20genetic%20testing%20should%20be%20performed%20in%20a%20CLIA-approved%20laboratory%20with%20results%20interpreted%20by%20a%20board-certified%20clinical%20molecular%20geneticist%20or%20molecular%20genetic%20pathologist%20or%20equivalent.%22%2C%22date%22%3A%222015-5%22%2C%22section%22%3A%22%22%2C%22partNumber%22%3A%22%22%2C%22partTitle%22%3A%22%22%2C%22DOI%22%3A%2210.1038%5C%2Fgim.2015.30%22%2C%22citationKey%22%3A%22%22%2C%22url%22%3A%22http%3A%5C%2F%5C%2Fwww.ncbi.nlm.nih.gov%5C%2Fpmc%5C%2Farticles%5C%2FPMC4544753%5C%2F%22%2C%22PMID%22%3A%2225741868%22%2C%22PMCID%22%3A%22PMC4544753%22%2C%22ISSN%22%3A%221098-3600%22%2C%22language%22%3A%22%22%2C%22collections%22%3A%5B%223W4D2W9R%22%2C%225KWTR87X%22%2C%22EJV8KV4Z%22%5D%2C%22dateModified%22%3A%222026-05-09T07%3A12%3A18Z%22%7D%7D%5D%7D
1.
MacArthur DG, Manolio TA, Dimmock DP, Rehm HL, Shendure J, Abecasis GR, et al. Guidelines for investigating causality of sequence variants in human disease. Nature [Internet]. 2014 Abril [cited 2015 June 23];508(7497):469–76. Available from: http://www.nature.com/nature/journal/v508/n7497/full/nature13127.html
1.
Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, et al. Standards and Guidelines for the Interpretation of Sequence Variants: A Joint Consensus Recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med [Internet]. 2015 May [cited 2016 Sept 6];17(5):405–24. Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4544753/