Specifications of the ACMG/AMP variant curation guidelines for the analysis of germline
            <i>CDH1</i>
            sequence variants

Lee, Kristy; Krempely, Kate; Roberts, Maegan E.; Anderson, Michael J.; Carneiro, Fátima; Chao, Elizabeth; Dixon, Katherine; Figueiredo, Joana; Ghosh, Rajarshi; Huntsman, David G.; Kaurah, Pardeep; Kesserwan, Chimene; Landrith, Tyler; Li, Shuwei; Mensenkamp, Arjen R.; Oliveira, Carla; Pardo, Carolina E.; Pesaran, Tina; Richardson, Matthew; Slavin, Thomas P.; Spurdle, Amanda B.; Trapp, Mackenzie; Witkowski, Leora; Yi, Charles S.; Zhang, Liying; Plon, Sharon E.; Schrader, Kasmintan A.; Karam, Rachid

doi:10.1002/humu.23650

Cited by 151 publications

(168 citation statements)

References 55 publications

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“…PS3 score was assigned for variants with a minigene result “Impact on splicing”, PS3_supporting for “Mild impact on splicing”. PP2, PP4 and PP5 criteria were not used, consistent with several other recent updates to the original ACMG criteria (Gelb et al 2018; Lee et al 2018; Kelly et al 2018). PP3 score was assigned for variants with REVEL score above 0.7.…”

Section: Methodsmentioning

confidence: 99%

Splicing impact of deep exonic missense variants in CAPN3 explored systematically by minigene functional assay

Dionnet

Defour

Silva

et al. 2020

Preprint

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Improving the accuracy of variant interpretation during diagnostic sequencing is a major goal for genomic medicine. In order to explore an often overlooked splicing effect of missense variants, we developed the functional assay (“minigene”) for the majority of exons of CAPN3, the gene responsible for Limb Girdle Muscular Dystrophy (LGMD). By systematically screening 21 missense variants distributed along the gene, we found that eight clinically relevant missense variants located at a certain distance from the exon/intron borders (deep exonic missense variants) disrupted normal splicing of CAPN3 exons. Several recent machine learning based computational tools failed to predict splicing impact for the majority of these deep exonic missense variants, highlighting the importance of including variants of this type in the training sets during the future algorithm development. Overall, 24 variants in CAPN3 gene were explored, leading to the change in the ACMG classification of seven of them when results of the “minigene” functional assay were taken into account. Our findings reveal previously unknown splicing impact of several clinically important variants in CAPN3 and draw attention to the existence of deep exonic variants with a disruptive effect on gene splicing that could be overlooked by the current approaches in clinical genetics.

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Section: Methodsmentioning

confidence: 99%

Splicing impact of deep exonic missense variants in CAPN3 explored systematically by minigene functional assay

Dionnet

Defour

Silva

et al. 2020

Preprint

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“…Moreover, a moderate strength level (rather than a strong level) should be assigned if a premature stop is downstream of NM_004360.3:c.2506G>T (p.Glu836Ter). 13 Second, the ClinGen PTEN Expert Panel recommended c.1121 position within exon 9 (NM_000314.4) as the 3’ boundary for PVS1_VeryStrong. 14 Third, the ClinGen Inherited Cardiomyopathy Expert Panel assigned a moderate weight (PVS1_Moderate) to an LoF variant in the MYH7 gene and removed the PVS1_VeryStrong rating.…”

Section: Methodsmentioning

confidence: 99%

“…The ClinGen Expert Panels also proposed disease/gene-specific PVS1 recommendations, including germline CDH1 , 13 PTEN , 14 and MYH7 -associated inherited cardiomyopathies. 15 For variants in these genes/diseases, PVS1 interpretation should follow the gene/disease-specific recommendations rather than the PVS1 evidence strength levels of ClinGen’s SVI Working Group, which are meant to provide general guidance across all diseases.…”

Section: Introductionmentioning

confidence: 99%

AutoPVS1: An automatic classification tool for PVS1 interpretation of null variants

Xiang

Peng

2019

Preprint

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Null variants are prevalent within human genome, and their accurate interpretation is critical for clinical management. In 2018, the ClinGen Sequence Variant Interpretation (SVI) Working Group refined the only criterion (PVS1) for pathogenicity in the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP) guidelines. The refinement may improve interpretation consistency, but it also brings hurdles to biocurators because of the complicated workflows and multiple bioinformatics sources required. To address these issues, we developed an automatic classification tool called AutoPVS1 to streamline PVS1 interpretation. We assessed the performance of AutoPVS1 using 56 variants manually curated by ClinGen's SVI Working Group and achieved an interpretation concordance of 95% (53/56). A further analysis of 28,586 putative loss-of-function variants by AutoPVS1 demonstrated that at least 27.6% of them do not reach a very strong strength level, with 17.4% based on variant-specific issues and 10.2% on disease mechanism considerations. Moreover, 40.7% (1,918/4,717) of splicing variants were assigned a decreased PVS1 strength level, significantly higher than frameshift and nonsense variants. Our results reinforce the necessity of considering variant-specific issues and disease mechanisms in variant interpretation, and demonstrate that AutoPVS1 is an accurate, reproducible, and reliable tool which facilitates PVS1 interpretation and will thus be of great importance to curators.

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“…In response to calls to further standardize variant interpretation [3,4], the Clinical Genome Resource (ClinGen) established the Sequence Variant Interpretation Working Group (SVI) [5] and condition-specific Variant Curation Expert Panels (VCEPs) to refine ACMG/AMP guidelines for each evidence criterion [6]. To date, six VCEPs have published recommendations, including their assay validation requirements and which assays were ultimately approved for PS3/BS3 evidence application [7][8][9][10][11][12]. VCEP-approved assays varied greatly and included splicing assays, animal and cellular models, and different in vitro systems [Kanavy et al, submitted].…”

Section: Introductionmentioning

confidence: 99%

Recommendations for application of the functional evidence PS3/BS3 criterion using the ACMG/AMP sequence variant interpretation framework

Brnich

Tayoun

Couch³

et al. 2019

Preprint

193

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Background:The American College of Medical Genetics and Genomics (ACMG)/Association for Molecular Pathology (AMP) clinical variant interpretation guidelines established criteria (PS3/BS3) for functional assays that specified a "strong" level of evidence. However, they did not provide detailed guidance on how functional evidence should be evaluated, and differences in the application of the PS3/BS3 codes is a contributor to variant interpretation discordance between laboratories. This recommendation seeks to provide a more structured approach to the assessment of functional assays for variant interpretation and guidance on the use of various levels of strength based on assay validation. Methods: The Clinical Genome Resource (ClinGen) Sequence Variant Interpretation (SVI)Working Group used curated functional evidence from ClinGen Variant Curation Expert Paneldeveloped rule specifications and expert opinions to refine the PS3/BS3 criteria over multiple inperson and virtual meetings. We estimated odds of pathogenicity for assays using various numbers of variant controls to determine the minimum controls required to reach moderate level evidence. Feedback from the ClinGen Steering Committee and outside experts were incorporated into the recommendations at multiple stages of development. Results:The SVI Working Group developed recommendations for evaluators regarding the assessment of the clinical validity of functional data and a four-step provisional framework to determine the appropriate strength of evidence that can be applied in clinical variant interpretation. These steps are: 1. Define the disease mechanism; 2. Evaluate applicability of general classes of assays used in the field; 3. Evaluate validity of specific instances of assays; 4.Apply evidence to individual variant interpretation. We found that a minimum of eleven total 4 pathogenic and benign variant controls are required to reach moderate-level evidence in the absence of rigorous statistical analysis. Conclusions:The recommendations and approach to functional evidence evaluation described here should help clarify the clinical variant interpretation process for functional assays. Further, we hope that these recommendations will help develop productive partnerships with basic scientists who have developed functional assays that are useful for interrogating the function of a variety of genes.

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Specifications of the ACMG/AMP variant curation guidelines for the analysis of germline CDH1 sequence variants

Cited by 151 publications

References 55 publications

Splicing impact of deep exonic missense variants in CAPN3 explored systematically by minigene functional assay

Splicing impact of deep exonic missense variants in CAPN3 explored systematically by minigene functional assay

AutoPVS1: An automatic classification tool for PVS1 interpretation of null variants

Recommendations for application of the functional evidence PS3/BS3 criterion using the ACMG/AMP sequence variant interpretation framework

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