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Abstract Details

Assessing ACMG Criteria for the Classification of Reported ALS Gene Mutations: Utility, Pitfalls, and Recommendations
Neuromuscular and Clinical Neurophysiology (EMG)
N2 - Neuroscience in the Clinic: Interpretations of Genetic Results (2:00 PM-2:15 PM)
001

Panel or whole exome sequencing is often utilized in the diagnostic work-up of ALS, increasing the need for accurate variant interpretation and reporting.  

To assess the utility of the American College of Medical Genetics (ACMG) guidelines for ALS (amyotrophic lateral sclerosis)-associated genes and propose recommendations to minimize the number of variants of unknown significance (VOUS). 

Variants in ALS-associated genes (ANXA11, ALS2, CCNF, CHCHD10, FUS, OPTN, NEK1, PFN1, SOD1, TARDBP, TBK1, UBQLN2, VAPB, and VCP) were sourced from public databases and reviewed using ACMG guidelines.  Consensus classifications were achieved using a modified Delphi approach.  Inter-rater reliability was assessed (k-alpha statistic).  ‘Meta’ in silico prediction algorithms – integrative “ensemble” prediction scores - were evaluated.  ALS-specific and gene-specific criteria were identified and utilized to estimate whether VOUS were more likely benign or pathogenic.

Final mean k-alpha was 0.91 (95% CI 0.87-0.95).  Only 19% of reported ALS variants met criteria for Pathogenic/Likely Pathogenic.  78% of variants were VOUS using ACMG criteria.  Criteria most relevant to pathogenicity were i) absence of variant from population databases, ii) novel missense variant, iii) computational evidence of pathogenicity.  Many criteria were only rarely applicable in ALS.  Gene-specific criteria included: i) identification of null variants (ALS2, OPTN, TBK1), iii) mutational hotspots (FUS, TARDBP, UBQLN2, VCP), iii) co-segregation of variant with disease (PFN1, VCP).  Relaxing the ACMG criteria with ALS-specific or gene-specific information allowed us to reclassify 77% of VOUS toward ‘Likely Pathogenic’ or ‘Likely Benign’.  

While ACMG criteria are a good starting point for the classification of variants in ALS genes, they leave many variants as VOUS.   We outline a set of disease and gene-specific issues for common ALS genes that guide variant interpretation beyond those provided by ACMG criteria and provide additional diagnostic interpretation of variants to help inform patients and families.

Authors/Disclosures
Danielle J. Leighton, MD
PRESENTER
No disclosure on file
No disclosure on file
Helaina Lehrer, MD (South Shore University Hospital Department of Neurosurgery) Dr. Lehrer has nothing to disclose.
Suvankar Pal No disclosure on file
Siddharthan Chandran No disclosure on file
No disclosure on file
Matthew Harms, MD (Columbia) Dr. Harms has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Biogen. Dr. Harms has received personal compensation in the range of $50,000-$99,999 for serving as a Consultant for Muscular Dystrophy Association. Dr. Harms has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Invitae. Dr. Harms has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Variant Bio. Dr. Harms has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Sarepta. Dr. Harms has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Amylyx. Dr. Harms has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for uniQure. Dr. Harms has received personal compensation in the range of $5,000-$9,999 for serving as an Expert Witness for Littlepage Booth. Dr. Harms has received personal compensation in the range of $500-$4,999 for serving as an Expert Witness for O'Connor First. Dr. Harms has received personal compensation in the range of $500-$4,999 for serving as an Expert Witness for Searcy Denney. Dr. Harms has received personal compensation in the range of $500-$4,999 for serving as an Expert Witness for Ford, Parshall & Baker LLC . The institution of Dr. Harms has received research support from ALS Association. The institution of Dr. Harms has received research support from Ionis. The institution of Dr. Harms has received research support from ALS Finding a Cure. The institution of Dr. Harms has received research support from Target ALS.