ACMG/AMP variant classification framework in arginase 1 deficiency: Implications for birth prevalence estimates and diagnostics.

PURPOSE

Arginase 1 (ARG1) deficiency manifests with hyperargininemia and progressive neurological impairment. Recent estimates of birth prevalence using allele frequencies of variants do not sufficiently distinguish benign from pathogenic variants. Additionally, ongoing discussions of reproductive carrier screening for diseases such as ARG1 creates a need for improved understanding of variant classification. Here, we incorporate American College of Medical Genetics and Genomics/Association for Molecular Pathology-developed guidelines for interpreting gene variants and in silico predictions to select allele frequencies for estimation of global birth prevalence of ARG1 deficiency.

METHODS

We interrogated Genome Aggregation Database and PubMed for published (defined as identified in patients with clinically defined arginase deficiency in scientific literature,  = 73) and unpublished variants (defined as variants present in Genome Aggregation Database, unique to , but not yet associated with clinical arginase deficiency,  = 302). American College of Medical Genetics and Genomics/Association for Molecular Pathology guidelines were applied to classify variants using Franklin Genoox artificial intelligence-powered platform and manual review.

RESULTS

Of 73 published variants, 16 classified as pathogenic, 30 as likely pathogenic, and 27 as variant of uncertain significance. Of 302 unpublished variants, 3 classified as pathogenic, 28 likely pathogenic, and 229 variant of uncertain significance. Mutant allele frequency estimates ranged from 17 to 266 per 100,000 and birth prevalence from 1 in 141,331 to 34,602,076.

CONCLUSION

We show that a large proportion of variants lack adequate evidence of pathogenicity. These findings underscore the significance of functional studies and accumulating clinical data for determination of variant pathogenicity and for improved understanding of global birth prevalence of ARG1 deficiency.