Curating the Clinical Genome 2024 ePoster Gallery-Specifying the ACMGAMP Sequence Variant Interpretation Guidelines for Congenital Myopathies

Specifying the ACMGAMP Sequence Variant Interpretation Guidelines for Congenital Myopathies

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The document discusses the ACMG/AMP Sequence Variant Interpretation Guidelines for Congenital Myopathies, focusing on five genes frequently involved in these conditions: ACTA1, NEB, MTM1, DNM2, and RYR1. It highlights the challenges of variant classification due to the numerous variants and varying degrees of evidence linking them to disease. The ClinGen ClinGen CM Variant Curation Expert Panel was established in 2020 to define criteria, review reported variants, and provide expert classifications for clinical significance following ACMG/AMP guidelines. Functional assays for each gene were proposed to assess variant impact, such as actin localization for ACTA1 and phosphatase activity for MTM1. The prevalence, mode of inheritance, penetrance, and genetic heterogeneity of these genes in congenital myopathies were also outlined. The expert panel approved specifications for PVS1 indications in four genes, emphasizing critical regions for protein function. Minor allele frequency cutoffs for benign variants were calculated for each gene. The document also details the locations of the 30 members of the Congenital Myopathies VCEP across different continents and the approval steps taken by the expert panel. Lastly, the REVEL score and impact on splicing using SpliceAI were considered for variant classification, along with the application of specific criteria for certain genes.

Keywords

ACMG/AMP Sequence Variant Interpretation Guidelines

Congenital Myopathies

ACTA1

NEB

MTM1

DNM2

RYR1

ClinGen ClinGen CM Variant Curation Expert Panel

Functional Assays

PVS1 Indications