Adapting the ACMG/AMP variant classification framework: A perspective from the ClinGen Hemoglobinopathy Variant Curation Expert Panel

Kountouris, Petros; Stephanou, Coralea; Lederer, Carsten W.; Traeger‐Synodinos, Joanne; Bento, Celeste; Harteveld, Cornelis L.; Fylaktou, Eirini; Koopmann, Tamara T.; Halim‐Fikri, Hashim; Michailidou, Kyriaki; Nfonsam, Landry; Waye, John S.; Zilfalil, Bin Alwi; Kleanthous, Marina

doi:10.1002/humu.24280

Cited by 23 publications

(22 citation statements)

References 35 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In 2015 was published what would become the international standard for DNA variants' classification, the ACMG/AMP guidelines [13]. These guidelines were meant to be applied to many different genes and conditions, and since then are being continually discussed and adapted [15][16][17][18][19][20].…”

Section: Discussionmentioning

confidence: 99%

The Study of a 231 French Patient Cohort Significantly Extends the Mutational Spectrum of the Two Major Usher Genes MYO7A and USH2A

Mansard

Baux

Vaché

et al. 2021

IJMS

View full text Add to dashboard Cite

Usher syndrome is an autosomal recessive disorder characterized by congenital hearing loss combined with retinitis pigmentosa, and in some cases, vestibular areflexia. Three clinical subtypes are distinguished, and MYO7A and USH2A represent the two major causal genes involved in Usher type I, the most severe form, and type II, the most frequent form, respectively. Massively parallel sequencing was performed on a cohort of patients in the context of a molecular diagnosis to confirm clinical suspicion of Usher syndrome. We report here 231 pathogenic MYO7A and USH2A genotypes identified in 73 Usher type I and 158 Usher type II patients. Furthermore, we present the ACMG classification of the variants, which comprise all types. Among them, 68 have not been previously reported in the literature, including 12 missense and 16 splice variants. We also report a new deep intronic variant in USH2A. Despite the important number of molecular studies published on these two genes, we show that during the course of routine genetic diagnosis, undescribed variants continue to be identified at a high rate. This is particularly pertinent in the current era, where therapeutic strategies based on DNA or RNA technologies are being developed.

show abstract

Section: Discussionmentioning

confidence: 99%

The Study of a 231 French Patient Cohort Significantly Extends the Mutational Spectrum of the Two Major Usher Genes MYO7A and USH2A

Mansard

Baux

Vaché

et al. 2021

IJMS

View full text Add to dashboard Cite

show abstract

“…Furthermore, we have used REVEL, which predict the pathogenicity of missense changes based on a combination of scores from 13 individual tools (Ioannidis et al 2016). The REVEL score can range from 0 to 1 and is recommended by CLINGEN consortium (https://www.clinicalgenome.org/) as a standalone meta-predictor for variant assessment (Kountouris et al 2021). The c.1464T>G p.(Cys488Trp) reached a significantly high score of 0.833; in general, a score >0.75 is considered evidence of pathogenicity.…”

Section: Variant Reassessment and Reclassificationmentioning

confidence: 99%

Reanalysis of a novel variant in the IGF1R gene in a family with variable pre-and postnatal growth retardation and dysmorphic features: benefits and feasibility of IUSM-URDC (Undiagnosed Rare Disease Clinic) program

Jacobs

Burns

Patel

et al. 2022

Cold Spring Harb Mol Case Stud

View full text Add to dashboard Cite

IGF1R-related disorders are associated with intrauterine growth restriction (IUGR), postnatal growth failure, short stature, microcephaly, developmental delay, and dysmorphic facial features. We report a patient who presented to medical genetics at 7 months of age with a history of intrauterine growth restriction (IUGR), poor feeding, mild developmental delays, microcephaly, and dysmorphic facial features. Whole exome sequencing revealed a novel c.1464 T>G (p.Cys488Trp) variant in the IGF1R gene, initially classified as a variation of uncertain significance (VUS). We enrolled the patient in URDC (Undiagnosed Rare Disease Clinic) and performed additional studies including deep phenotyping and familial segregation analysis, which demonstrated that the patient's IGF1R VUS was present in phenotypically similar family members. Furthermore, biochemical testing revealed an elevated serum IGF1 level consistent with abnormal IGF1 receptor function. Work-up resulted in the patient's variant being upgraded from a VUS to likely pathogenic. Our report expands the variant and phenotypic spectrum of IGF1R-related disorders and illustrates benefits and feasibility of reassessing a VUS beyond the initial molecular diagnosis by deep phenotyping, 3D modeling, additional biochemical testing and familial segregation studies through URDC, a multidisciplinary clinical program whose major goal is to end the diagnostic odyssey in patients with rare diseases.

show abstract

“…When should a pathologically relevant mutation be considered to be a "risk" variant rather than being "pathogenic" in its own right? Various adaptations and refinements of the ACMG guidelines have previously been made in the context of secondary findings derived from clinical exome and genome sequencing [4] as well as in the context of different genes/diseases [5][6][7][8][9][10][11][12][13][14] or specific variant types [15]. In addition, a comprehensive refinement of the ACMG variant classification criteria in terms of 40,000 clinically observed variants has also been made [16].…”

Section: Introductionmentioning

confidence: 99%

Expanding ACMG variant classification guidelines into a general framework

et al. 2022

View full text Add to dashboard Cite

Background The American College of Medical Genetics and Genomics (ACMG)-recommended five variant classification categories (pathogenic, likely pathogenic, uncertain significance, likely benign, and benign) have been widely used in medical genetics. However, these guidelines are fundamentally constrained in practice owing to their focus upon Mendelian disease genes and their dichotomous classification of variants as being either causal or not. Herein, we attempt to expand the ACMG guidelines into a general variant classification framework that takes into account not only the continuum of clinical phenotypes, but also the continuum of the variants’ genetic effects, and the different pathological roles of the implicated genes. Main body As a disease model, we employed chronic pancreatitis (CP), which manifests clinically as a spectrum from monogenic to multifactorial. Bearing in mind that any general conceptual proposal should be based upon sound data, we focused our analysis on the four most extensively studied CP genes, PRSS1, CFTR, SPINK1 and CTRC. Based upon several cross-gene and cross-variant comparisons, we first assigned the different genes to two distinct categories in terms of disease causation: CP-causing (PRSS1 and SPINK1) and CP-predisposing (CFTR and CTRC). We then employed two new classificatory categories, “predisposing” and “likely predisposing”, to replace ACMG’s “pathogenic” and “likely pathogenic” categories in the context of CP-predisposing genes, thereby classifying all pathologically relevant variants in these genes as “predisposing”. In the case of CP-causing genes, the two new classificatory categories served to extend the five ACMG categories whilst two thresholds (allele frequency and functional) were introduced to discriminate “pathogenic” from “predisposing” variants. Conclusion Employing CP as a disease model, we expand ACMG guidelines into a five-category classification system (predisposing, likely predisposing, uncertain significance, likely benign, and benign) and a seven-category classification system (pathogenic, likely pathogenic, predisposing, likely predisposing, uncertain significance, likely benign, and benign) in the context of disease-predisposing and disease-causing genes, respectively. Taken together, the two systems constitute a general variant classification framework that, in principle, should span the entire spectrum of variants in any disease-related gene. The maximal compliance of our five-category and seven-category classification systems with the ACMG guidelines ought to facilitate their practical application.

show abstract

Adapting the ACMG/AMP variant classification framework: A perspective from the ClinGen Hemoglobinopathy Variant Curation Expert Panel

Cited by 23 publications

References 35 publications

The Study of a 231 French Patient Cohort Significantly Extends the Mutational Spectrum of the Two Major Usher Genes MYO7A and USH2A

The Study of a 231 French Patient Cohort Significantly Extends the Mutational Spectrum of the Two Major Usher Genes MYO7A and USH2A

Reanalysis of a novel variant in the IGF1R gene in a family with variable pre-and postnatal growth retardation and dysmorphic features: benefits and feasibility of IUSM-URDC (Undiagnosed Rare Disease Clinic) program

Expanding ACMG variant classification guidelines into a general framework

Contact Info

Product

Resources

About