Stepwise ABC system for classification of any type of genetic variant

Abstract

The American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG-AMP) system for variant classification is score based with five classes: benign, likely benign, variant of unknown significance (VUS), likely pathogenic, and pathogenic. Here, we present a variant classification model that can be an add-on or alternative to ACMG classification: A stepwise system that can classify any type of genetic variant (e.g., hypomorphic alleles, imprinted alleles, copy number variants, runs of homozygosity, enhancer variants, and variants related to traits). We call it the ABC system because classification is first functional (A), then clinical (B), and optionally a standard comment that fits the clinical question is selected (C). Both steps A and B have 1–5 grading when knowledge is sufficient, if not, class “zero” is assigned. Functional grading (A) only concerns biological consequences with the stages normal function (1), likely normal function (2), hypothetical functional effect (3), likely functional effect (4), and proven functional effect (5). Clinical grading (B) is genotype–phenotype focused with the stages “right type of gene” (1), risk factor (2), and pathogenic (3–5, depending on penetrance). Both grades are listed for each variant and combined to generate a joint class ranging from A to F. Importantly, the A–F classes are linked to standard comments, reflecting laboratory or national policy. In step A, the VUS class is split into class 0 (true unknown) and class 3 (hypothetical functional effect based on molecular predictions or de novo occurrence), providing a rationale for variant-of-interest reporting when the clinical picture could fit the finding. The system gives clinicians a better guide to variant significance.

Variant Selection and Interpretation: An Example of Modified VarSome Classifier of ACMG Guidelines in the Diagnostic Setting

“…This would lead the geneticist to downgrade the criterion to Supporting or even exclude it, according to the internal checklist ( Table 2 ), without changing the variant’s final interpretation ( Figure 3 ). This might not seem important in the light of the ACMG five-tier classification system; however, it may become relevant for the finer differentiation of VUS (from ice-cold to hot) proposed by the ACGS 2020 guidelines [ 35 , 36 ].…”

A defect in molybdenum cofactor binding causes an attenuated form of sulfite oxidase deficiency

“…The mutation results in a substitution of the highly conserved Arginine 366 to a histidine (Figure 1C), which is part of the structural motive that coordinates the Moco‐phosphate moiety in mature SO (Figure 1D). Together with clinical phenotype and the biochemical profile, we consider this variant as pathogenic and disease causing according to the latest ESHG Guidelines 29 …”

AnFiSA: An open-source computational platform for the analysis of sequencing data for rare genetic disease

“…The number of variants of uncertain significance (VUS) were also decreased [13], where the VUS detection rate was linked to the quality and efficacy of variant curation [13], [14]. Alternative classification approaches are also being explored [15].…”

“…The number of variants of uncertain significance (VUS) were also decreased [13], where the VUS detection rate was linked to the quality and efficacy of variant curation [13], [14]. Alternative classification approaches are also being explored [15]. Though a number of computational tools emerged for variant interpretation, the typical research or diagnostic problem consists of identifying the pathogenic mutation amongst the myriad of allelic variants in the patient's genome.…”