Biology subjects

Johnston, J. J.

Publications and source records attributed to Johnston, J. J..

3 recordsLinked to original sources

bioRxiv2025

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

PurposeThe return of secondary findings (SF) is well-established in clinical testing and is increasingly employed in clinical research testing. Variant classification can be challenging due to the lack of monogenic disease entity (MDE, defined as a gene-phenotype pair) specific variant classification recommendations. A key criterion for variant classification is disease allele frequency thresholds (DAFTs), which are not established for all MDEs recommended for the return of SF. MethodsWe calculated DAFTs for SF MDEs considering prevalence, gene contribution, and penetrance. ACMG criterion BS1 was set at the calculated DAFT value, with BA1 set at ten times the calculated DAFT. For genes associated with multiple SF MDEs without clear genotype-phenotype correlation, DAFT values were combined. GnomAD Grpmax filtering allele frequencies (FAF) for pathogenic/likely pathogenic classified variants were compared to calculated thresholds. ResultsWe determined BS1 and BA1 values for 58 SF MDEs (47 genes). No pathogenic/likely pathogenic variant Grpmax FAF was greater than the relevant MDE-specific BA1. ConclusionSetting BA1 and BS1 thresholds should improve variant classification consistency and reduce misclassifications. For SF MDEs without current ClinGen Variant Curation Expert Panel (VCEP) specifications, these frequency specifications can be used until full criteria are available.

genetics↗

bioRxiv2022

Updated Variant Curation Expert Panel Criteria and Pathogenicity Classifications for 251 Variants for RYR1-related Malignant Hyperthermia Susceptibility

The ClinGen malignant hyperthermia susceptibility (MHS) variant curation expert panel specified the ACMG/AMP criteria for RYR1-related MHS and a pilot analysis of 84 variants was published. We have now classified an additional 251 variants for RYR1-related MHS according to current ClinGen standards and updated the criteria where necessary. Criterion PS4 was modified such that individuals with multiple RYR1 variants classified as pathogenic (P), likely pathogenic (LP) or variant of uncertain significance (VUS) were not considered as providing evidence for pathogenicity. Critera PS1 and PM5 were revised to consider LP variants at the same amino acid residue as providing evidence for pathogenicity at reduced strength. Finally, PM1 was revised such that if PS1 or PM5 are used PM1, if applicable, should be downgraded to supporting. Of the 251 RYR1 variants, 42 were classified as P/LP, 16 as B/LB, and 193 as VUS. The primary driver of 176 VUS classifications was insufficient evidence supporting pathogenicity, rather than evidence against pathogenicity. Functional data supporting PS3/BS3 was identified for only 13 variants. Based on the posterior probabilities of pathogenicity and variant frequencies in gnomAD, we estimated the prevalence of individuals with RYR1-related MHS pathogenic variants to be between 1/300 and 1/1,075, considerably higher than current estimates. We have updated ACMG/AMP criteria for RYR1-related MHS and classified 251 variants. We suggest that prioritization of functional studies is needed to resolve the large number of VUS classifications and allow for appropriate risk assessment. RYR1-related MHS pathogenic variants are likely to be more common than currently appreciated.

genetics↗

bioRxiv2020

Variant Curation Expert Panel Recommendations for RYR1 Pathogenicity Assertions in Malignant Hyperthermia Susceptibility

PurposePrevention of malignant hyperthermia (MH) requires an understanding of RYR1 variant pathogenicity to assess the risk of exposure to triggering agents. Personalized medicine, especially secondary findings and eventually genomic screening, will contribute toward this goal. MethodsWe specified ACMG/AMP criteria for variant interpretation for RYR1 and MH. Proposed rules were piloted on 84 variants. We applied quantitative evidence calibration for several criteria using likelihood ratios based on the Bayesian framework. ResultsSeven ACMG/AMP criteria were adopted without changes, ten were adopted with RYR1-specific modifications, and nine were dropped. The in silico (PP3 and BP4) and hot spot criteria (PM1) were evaluated quantitatively. REVEL gave an OR of 23:1 for PP3 and 16:1 for BP4 using trichotomized cut-offs of >0.85 (pathogenic) and <0.5 (benign). The PM1 hotspot criterion had an OR of 24:1. PP3 and PM1 were implemented at moderate strength. Applying the revised ACMG criteria to 44 recognized MH variants, 30 were assessed as pathogenic, 12 as likely pathogenic, and two as VUS. ConclusionCuration of these variants will facilitate interpretation of RYR1/MH genomic testing results, which is especially important for secondary findings analyses. Our approach to quantitatively calibrating criteria are generalizable to other variant curation expert panels.

genetics↗