ClinGen Variant Curation Expert Panel experiences and standardized processes for disease and gene‐level specification of the ACMG/AMP guidelines for sequence variant interpretation

Genome‐scale sequencing creates vast amounts of genomic data, increasing the challenge of clinical sequence variant interpretation. The demand for high‐quality interpretation requires multiple specialties to join forces to accelerate the interpretation of sequence variant pathogenicity. With over 600 international members including clinicians, researchers, and laboratory diagnosticians, the Clinical Genome Resource (ClinGen), funded by the National Institutes of Health, is forming expert groups to systematically evaluate variants in clinically relevant genes. Here, we describe the first ClinGen variant curation expert panels (VCEPs), development of consistent and streamlined processes for establishing new VCEPs, and creation of standard operating procedures for VCEPs to define application of the ACMG/AMP guidelines for sequence variant interpretation in specific genes or diseases. Additionally, ClinGen has created user interfaces to enhance reliability of curation and a Sequence Variant Interpretation Working Group (SVI WG) to harmonize guideline specifications and ensure consistency between groups. The expansion of VCEPs represents the primary mechanism by which curation of a substantial fraction of genomic variants can be accelerated and ultimately undertaken systematically and comprehensively. We welcome groups to utilize our resources and become involved in our effort to create a publicly accessible, centralized resource for clinically relevant genes and variants.

• Publication year

  2018

• Venue

  Human Mutation

• Publication date

  2018-10-11

• Fields of study

  Biology, Medicine, Computer Science

• Identifiers
  DOI 10.1002/humu.23645PMID 30311389PMCID PMC6225902
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• ACGS Best Practice Guidelines for Variant Classification 2019

  2019cited by this paper
• ClinGen’s RASopathy Expert Panel Consensus Methods for Variant Interpretation

  2018cited by this paper
• Recommendations for Interpreting the Loss of Function PVS1 ACMG/AMP Variant Criteria

  2018cited by this paper
• Updated recommendation for the benign stand‐alone ACMG/AMP criterion

  2018cited by this paper
• Unique aspects of sequence variant interpretation for inborn errors of metabolism (IEM): The ClinGen IEM Working Group and the Phenylalanine Hydroxylase Gene

  2018cited by this paper
• Adaptation and validation of the ACMG/AMP variant classification framework for MYH7-associated inherited cardiomyopathies: recommendations by ClinGen’s Inherited Cardiomyopathy Expert Panel

  2018cited by this paper
• Gene‐specific criteria for PTEN variant curation: Recommendations from the ClinGen PTEN Expert Panel

  2018cited by this paper
• Points to consider for sharing variant-level information from clinical genetic testing with ClinVar

  2018cited by this paper
• Development of Clinical Domain Working Groups for the Clinical Genome Resource (ClinGen): Lessons Learned and Plans for the Future

  2018cited by this paper
• Distinguishing pathogenic mutations from background genetic noise in cardiology: The use of large genome databases for genetic interpretation

  2018influential reference
• Recommendations for interpreting the loss of function PVS1 ACMG/AMP variant criterion

  2018cited by this paper
• Data sharing as a national quality improvement program: reporting on BRCA1 and BRCA2 variant-interpretation comparisons through the Canadian Open Genetics Repository (COGR)

  2017cited by this paper
• Clinical Laboratories Collaborate to Resolve Differences in Variant Interpretations Submitted to ClinVar

  2017cited by this paper
• Care in Specialized Centers and Data Sharing Increase Agreement in Hypertrophic Cardiomyopathy Genetic Test Interpretation

  2017cited by this paper
• A Taxonomy of Medical Uncertainties in Clinical Genome Sequencing

  2017cited by this paper
• Genetics of Phenylketonuria: Then and Now

  2016cited by this paper
• Recommendations for the integration of genomics into clinical practice

  2016cited by this paper
• Performance of ACMG-AMP Variant-Interpretation Guidelines among Nine Laboratories in the Clinical Sequencing Exploratory Research Consortium.

  2016cited by this paper
• Performance of ACMG-AMP Variant-Interpretation Guidelines among Nine Laboratories in the Clinical Sequencing Exploratory Research Consortium.

  2016cited by this paper
• Gene Variant Databases and Sharing: Creating a Global Genomic Variant Database for Personalized Medicine

  2016cited by this paper
• Reassessment of Genomic Sequence Variation to Harmonize Interpretation for Personalized Medicine.

  2016cited by this paper
• KBG Syndrome: A Case Report and Longitudinal Assessment of Long‐Acting Recombinant Human Growth Hormone Therapy

  2015cited by this paper
• The Genetic Basis of Mendelian Phenotypes: Discoveries, Challenges, and Opportunities.

  2015cited by this paper
• ClinGen--the Clinical Genome Resource.

  2015cited by this paper
• ClinVar: public archive of interpretations of clinically relevant variants

  2015cited by this paper
• Implementing genomic medicine in the clinic: the future is here

  2013cited by this paper

• Phenotypic Variability Associated with Jagunal Homolog 1 (JAGN1) Deficiency Caused by the c.63G>T Variant.

  2026cites this paper
• Identifying TMEM127-deficient pheochromocytomas/paragangliomas via RET overexpression by immunohistochemistry

  2026cites this paper
• ACVI-Med, an open source variant interpretation tool for medical genomics.

  2026cites this paper
• Population and family data support TNNT2 p.Arg288Cys as an intermediate effect variant in hypertrophic cardiomyopathy.

  2026cites this paper
• Improving genetic diagnosis of hereditary tumor syndromes: From expanded gene panels to functional genomics.

  2025cites this paper
• Functional characterization of SDHB variants clarifies hereditary pheochromocytoma and paraganglioma risk and genotype-phenotype relationships

  2025cites this paper
• Incidence of non-colorectal/endometrial malignancies in individuals with Lynch syndrome: a retrospective cohort study

  2025cites this paper
• Reduced penetrance of COL1A1/2 pathogenic variants linked with osteogenesis imperfecta: analysis of a large population cohort

  2025cites this paper
• Real-world effects of using gnomAD 4.1.0 and AllofUs population reference datasets on reporting of variants of uncertain significance.

  2025cites this paper
• Specifications of the ACMG/AMP variant curation guidelines for the analysis of germline PALB2 sequence variants.

  2025cites this paper
• Variant classification of hereditary cancer genes is affected by genomic underrepresentation of admixed populations

  2025cites this paper
• Complexities in Variant Analysis, Classification, and Interpretation in Kidney Disease-Related Genes.

  2025cites this paper
• Detecting likely germline variants during tumor-based molecular profiling

  2025cites this paper
• Identification of LRFN1 as a novel synaptopathy gene in a child with autism

  2025cites this paper
• Survey of Demographics, Training, Duties, and Professional Development for Variant Scientists in Genomic Medicine

  2025cites this paper
• Adaptation of ACMG/AMP Guidelines for Clinical Classification of BMPR2 Variants in Pulmonary Arterial Hypertension Resolves Variants of Unclear Pathogenicity in ClinVar

  2025cites this paper
• Identification of a novel mutation in RBM10 gene: A case report of TARP syndrome with deletion mutation

  2025cites this paper
• Validating data from Multiplex Assays of Variant Effect - A CanVIG-UK National Survey of NHS Clinical Scientists

  2025cites this paper
• Consultation informs strategies for improving the use of functional evidence in variant classification.

  2025cites this paper
• Diagnosis, management, and monitoring of interleukin-1 mediated diseases in Central and Eastern Europe: real-world data

  2025cites this paper
• A series of reviews in familial cancer: genetic cancer risk in context variants of uncertain significance in MMR genes: which procedures should be followed?

  2025cites this paper
• Updated ACMG/AMP specifications for variant interpretation and gene curations from the ClinGen RASopathy expert panels

  2025cites this paper
• Genetic analysis of four cases of Poirier Bienvenu neurodevelopmental syndrome associated with CSNK2B variant

  2025cites this paper
• Reassessment of FBN1 variants of uncertain significance using updated ClinGen guidance for PP1/BS4 and PP4 criteria

  2025cites this paper
• Accelerating genetic diagnostics in retinitis pigmentosa: implementation of a semi-automated bespoke cohort analysis workflow for Hong Kong Genome Project

  2025cites this paper
• Precision genome editing and in-cell measurements of oxidative DNA damage repair enable functional and mechanistic characterization of cancer-associated MUTYH variants

  2025cites this paper
• Genomic landscape and molecularly informed therapy in thymic carcinoma and other advanced thymic epithelial tumors.

  2025cites this paper
• An Actor-Critic Reinforcement Learning Framework for Variant Evidence Interpretation

  2025cites this paper
• Updated MDSGene review on the clinical and genetic spectrum of LRRK2 variants in Parkinson´s disease

  2025cites this paper
• Leveraging cancer mutation data to inform the pathogenicity classification of germline missense variants

  2025cites this paper
• Reclassification of VUS in BRCA1 and BRCA2 using the new BRCA1/BRCA2 ENIGMA track set demonstrates the superiority of ClinGen ENIGMA Expert Panel specifications over the standard ACMG/AMP classification system

  2025cites this paper
• 17.6% of patients in a German cohort with exocrine pancreatic cancer were diagnosed with a genetic tumor syndrome—a case for universal genetic testing?

  2025cites this paper
• Novel variants in STAG2 and PKD1 associate with multiple congenital malformations and autosomal dominant polycystic kidney disease in a Chinese family: A case report and literature review

  2025cites this paper
• Congenital Anomalies in a Neonate With Partial Monosomy of Chromosome 21 q Arm: A Case Report

  2025cites this paper
• Understanding variants of unknown significance and classification of genomic alterations

  2024cites this paper
• Consultation informs strategies to improve functional evidence use in variant classification

  2024cites this paper
• Adaptation of ACMG/AMP guidelines for clinical classification of BMPR2 variants in Pulmonary Arterial Hypertension resolves variants of unclear pathogenicity in ClinVar.

  2024cites this paper
• Virtual Gene Panels Have a Superior Diagnostic Yield for Inherited Rare Diseases Relative to Static Panels.

  2024cites this paper
• Automated variant re-evaluation is labor-balanced and gives clinically relevant results: hereditary cardiac disease as a use case.

  2024cites this paper
• The Clinical Genome Resource (ClinGen): Advancing genomic knowledge through global curation.

  2024cites this paper
• A call to action to scale up research and clinical genomic data sharing

  2024cites this paper
• Large-scale application of ClinGen-InSiGHT APC-specific ACMG/AMP variant classification criteria leads to substantial reduction in VUS

  2024cites this paper
• A novel human SDHA‑knockout cell line model for the functional analysis of clinically‑relevant SDHA variants.

  2024cites this paper
• Update on Genetic Counselor Practice and Recommendations for Pediatric Cancer Predisposition Evaluation and Surveillance.

  2024cites this paper
• Classification of Variants of Reduced Penetrance in High Penetrance Cancer Susceptibility Genes: Framework for Genetics Clinicians and Clinical Scientists by CanVIG-UK (Cancer Variant Interpretation Group-UK)

  2024cites this paper
• Autosomal Recessive Guanosine Triphosphate Cyclohydrolase I Deficiency: Redefining the Phenotypic Spectrum and Outcomes

  2024cites this paper
• Curating Genetic Associations With Rheumatologic Autoimmune Diseases to Improve Patient Outcomes

  2024cites this paper
• Significance of utilizing in silico structural analysis and phenotypic data to characterize phenylalanine hydroxylase variants: A PAH landscape.

  2024cites this paper
• Variant classification changes over time in the clinical molecular diagnostic laboratory setting

  2024cites this paper
• Design and Pilot Results from Million Veteran Program Return Of Actionable Genetic Results (MVP-ROAR) Study.

  2024cites this paper
• Systematic large-scale application of ClinGen InSiGHT APC-specific ACMG/AMP variant classification criteria substantially alleviates the burden of variants of uncertain significance in ClinVar and LOVD databases

  2024cites this paper
• The PS4-likelihood ratio calculator: flexible allocation of evidence weighting for case-control data in variant classification

  2024cites this paper
• Datasets-Based IMPDH1 Revisited: Heterozygous Missense Variants for Dominant Retinitis Pigmentosa While Truncation Variants Are Likely Non-Pathogenic

  2024cites this paper
• Landscape of genomic structural variations in Indian population-based cohorts: Deeper insights into their prevalence and clinical relevance

  2024cites this paper
• Genebe.net: Implementation and validation of an automatic ACMG variant pathogenicity criteria assignment

  2024cites this paper
• ACMG/AMP variant classification framework in arginase 1 deficiency: Implications for birth prevalence estimates and diagnostics

  2024cites this paper
• Evidence-based recommendations for gene-specific ACMG/AMP variant classification from the ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel

  2024cites this paper
• Evaluating ClinGen variant curation expert panels' application of PVS1 code.

  2024cites this paper
• Genomic autopsy to identify underlying causes of pregnancy loss and perinatal death

  2023cites this paper
• Assessing Protein Surface-Based Scoring for Interpreting Genomic Variants

  2023cites this paper
• Variant Classification for Pompe disease; ACMG/AMP specifications from the ClinGen Lysosomal Diseases Variant Curation Expert Panel.

  2023cites this paper
• Re-evaluation of a Fibrillin-1 Gene Variant of Uncertain Significance Using the ClinGen Guidelines

  2023cites this paper
• Digenic variant interpretation with hypothesis-driven explainable AI

  2023cites this paper
• A novel case of two siblings harbouring homozygous variant in the NEUROG1 gene with autism as an additional phenotype: a case report

  2023cites this paper
• Introducing return of results in the Million Veteran Program: Design and pilot results of the MVP-ROAR Familial Hypercholesterolemia Study

  2023cites this paper
• Gene-specific ACMG/AMP classification criteria for germline APC variants: recommendations from the ClinGen InSiGHT Hereditary Colorectal Cancer / Polyposis Variant Curation Expert Panel.

  2023cites this paper
• Reclassification of clinical exome data leads to significant clinical assessment changes in almost half of the patients

  2023cites this paper
• Genetic Characterization of Blood Group Antigens for Polynesian Heritage Norfolk Island Residents

  2023cites this paper
• Artificial intelligence-based approaches for the detection and prioritization of genomic mutations in congenital surgical diseases

  2023cites this paper
• Specifications of the ACMG/AMP guidelines for ACADVL variant interpretation.

  2023cites this paper
• Multidisciplinary molecular consultation increases the diagnosis of pediatric epileptic encephalopathy and neurodevelopmental disorders

  2023cites this paper
• Annual Review of Genomics and Human Genetics: DECIPHER: Improving Genetic Diagnosis Through Dynamic Integration of Genomic and Clinical Data

  2023cites this paper
• The functional impact of 1,570 individual amino acid substitutions in human OTC.

  2023cites this paper
• Specifications of the ACMG/AMP Variant Classification Guidelines for Germline DICER1 Variant Curation

  2023cites this paper
• Association of Reported Candidate Monogenic Genes With Lung Cancer Risk.

  2023cites this paper
• Systematic use of phenotype evidence in clinical genetic testing reduces the frequency of variants of uncertain significance

  2022cites this paper
• An oncogenic splice variant of PDGFRα in adult glioblastoma as a therapeutic target for selective CDK4/6 inhibitors

  2022cites this paper
• Landscape of pathogenic variants in six pre‐mRNA processing factor genes for retinitis pigmentosa based on large in‐house data sets and database comparisons

  2022cites this paper
• Specifications of the ACMG/AMP variant curation guidelines for myocilin: Recommendations from the clingen glaucoma expert panel

  2022cites this paper
• The Molecular Tumor Board Portal supports clinical decisions and automated reporting for precision oncology

  2022cites this paper
• Towards accurate and reliable resolution of structural variants for clinical diagnosis

  2022cites this paper
• Evolution of germline TP53 variant classification in children with cancer.

  2022cites this paper
• Adaptation of ACMG-ClinGen Technical Standards for Copy Number Variant Interpretation Concordance

  2022cites this paper
• Comprehensive analysis of recessive carrier status using exome and genome sequencing data in 1543 Southern Chinese

  2022cites this paper
• Inherited risk assessment and its clinical utility for predicting prostate cancer from diagnostic prostate biopsies

  2022cites this paper
• The patient with 41 reports: Analysis of laboratory exome sequencing reporting of a "virtual patient".

  2022cites this paper
• An Educational Assessment of Evidence Used for Variant Classification: A Report of the Association for Molecular Pathology.

  2022cites this paper
• Development of a clinical polygenic risk score assay and reporting workflow

  2022cites this paper
• The Clinical Variant Analysis Tool: Analyzing the evidence supporting reported genomic variation in clinical practice.

  2022cites this paper
• Primary Care Implementation of Genomic Population Health Screening Using a Large Gene Sequencing Panel

  2022cites this paper
• Genome interpretation using in silico predictors of variant impact

  2022cites this paper
• Pathogenicity Assignment of Variants in Genes Associated With Cardiac Channelopathies Evolve Toward Diagnostic Uncertainty

  2022cites this paper
• The global prevalence and ethnic heterogeneity of iron-refractory iron deficiency anaemia

  2022cites this paper
• Scalable Functional Assays for the Interpretation of Human Genetic Variation.

  2022cites this paper
• Case report: Rare among ultrarare—Clinical odyssey of a new patient with Ogden syndrome

  2022cites this paper
• Indications and utility of cardiac genetic testing in athletes.

  2022cites this paper
• Author Correction: Towards accurate and reliable resolution of structural variants for clinical diagnosis

  2022cites this paper
• Statistical evidence for high‐penetrance MODY‐causing genes in a large population‐based cohort

  2022cites this paper
• Systematic review of reported association studies of monogenic genes and bladder cancer risk and confirmation analysis in a large population cohort

  2022cites this paper
• Hereditary Diffuse Gastric Cancer: A 2022 Update

  2022cites this paper