Steven M. Harrison

Specification of frequency criteria for secondary findings genes to improve variant classification concordance

The paper establishes frequency criteria for secondary findings genes to improve variant classification consistency by setting disease allele frequency thresholds for 58 monogenic disease entities.

Extracting and calibrating evidence of variant pathogenicity from population biobank data

The paper uses population biobank data to identify and calibrate evidence of variant pathogenicity for 41 genes, finding that 2.6% of participants have rare variants with moderate or stronger evidence of pathogenicity.

Calibration of additional computational tools expands ClinGen recommendation options for variant classification with PP3/BP4 criteria

The paper calibrates three new computational tools for clinical variant classification, finding they provide evidence strength comparable to previously recommended tools.

Distinct rates of VUS reclassification are observed when subclassifying VUS by evidence level

The paper examines how variants of uncertain significance (VUS) are reclassified based on subclassification evidence levels across four clinical laboratories.

Assessment of the evidence yield for the calibrated PP3/BP4 computational recommendations

The paper assesses rare missense variants in genome sequences using PP3/BP4 evidence strength classifications and finds few variants meet strong or moderate criteria.

Clinical interpretation of KCNH2 variants using a robust PS3/BS3 functional patch clamp assay

The paper establishes a functional patch clamp assay to classify KCNH2 variants in LQTS, using Z-scores to inform ACMG criteria and correlate with clinical scores.

Advanced variant classification framework reduces the false positive rate of predicted loss of function (pLoF) variants in population sequencing data

This paper presents a framework to reduce false positives in predicted loss-of-function variants by analyzing LoF evasion mechanisms and adjusting ACMG/AMP guidelines.

The landscape of reported VUS in multi-gene panel and genomic testing: Time for a change

The paper analyzes VUS rates in genetic testing and finds lower rates in exome/genome sequencing compared to multi-gene panels, suggesting improvements in variant reporting practices.

APPLICATION OF THE ACMG/AMP FRAMEWORK TO CAPTURE EVIDENCE RELEVANT TO PREDICTED AND OBSERVED IMPACT ON SPLICING: RECOMMENDATIONS FROM THE CLINGEN SVI SPLICING SUBGROUP

The paper refines ACMG/AMP splicing variant classification codes using empirical evidence to improve consistency in variant pathogenicity classification.

Evidence-based calibration of computational tools for missense variant pathogenicity classification and ClinGen recommendations for clinical use of PP3/BP4 criteria

The paper calibrates computational tools for missense variant pathogenicity classification and provides evidence-based revisions to PP3/BP4 ACMG/AMP criteria.

Recommendations for clinical interpretation of variants found in non-coding regions of the genome

This paper provides recommendations for interpreting non-coding variants in clinical settings, adapting existing guidelines to account for their role in disease.

A calibrated functional patch clamp assay to enhance clinical variant interpretation in KCNH2-related long QT syndrome

This study uses a high-throughput patch-clamp assay to reclassify KCNH2 variants of uncertain significance, providing evidence for clinical interpretation.

Whole genome sequencing as an investigational device for return of hereditary disease risk and pharmacogenomic results as part of the All of Us Research Program

The paper describes the process of obtaining an FDA IDE for returning genomic results via WGS in the All of Us Research Program and presents validation results.

ClinGen Variant Curation Interface: A Variant Classification Platform for the Application of Evidence Criteria from ACMG/AMP Guidelines

The paper introduces the ClinGen Variant Curation Interface, a platform for applying ACMG/AMP guidelines to classify genetic variants, enabling collaboration and standardization in clinical variant interpretation.

Genetic Sex Validation for Sample Tracking in Clinical Testing

The paper validates genetic sex using a 96-SNP PCR panel to track samples in clinical testing and identify inconsistencies.

Creation of an Expert Curated Variant List for Clinical Genomic Test Development and Validation: A ClinGen and GeT-RM Collaborative Project

The paper curates a list of clinically important variants for use in clinical genomic test development and validation.

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

The paper provides structured recommendations for applying the PS3/BS3 functional evidence criteria in variant interpretation using the ACMG/AMP framework, including a four-step framework and minimum control requirements.

Response to Shah et al: Using high-resolution variant frequencies empowers clinical genome interpretation and enables investigation of genetic architecture

The paper responds to a critique of their variant filtering method, demonstrating its robustness and highlighting the benefits of using high-resolution variant frequencies for clinical genome interpretation.

Recommendations for Interpreting the Loss of Function PVS1 ACMG/AMP Variant Criteria

The paper provides refined recommendations for applying the PVS1 ACMG/AMP variant criteria to loss of function variants, addressing gaps in the original guideline through evaluation with curated variants.