Variant Classification of a Non-Protein Coding Gene: ACMG/AMP Specifications for RMRP from the Clinical Genome Resource Severe Combined Immunodeficiency Disease Variant Curation Expert Panel

ACMG/AMP specifications adapted for germline RMRP variant interpretation classified 6 variants as pathogenic, 10 as likely pathogenic, 7 as uncertain, and 4 as benign in cartilage-hair hypoplasia.

• Why it matters: ACMG/AMP was built mainly for protein-coding genes, leaving a gap for standardized interpretation of non-protein-coding RNA genes like RMRP in cartilage-hair hypoplasia, including SCID.
• What they did: A ClinGen SCID-VCEP subgroup reviewed all 28 ACMG/AMP evidence criteria for RMRP, retaining 15 and marking 13 not applicable, then pilot tested the specifications on 27 variants using population data, literature, computational predictions, and expert consensus.
• The result: The adapted framework modified criteria for nucleotide-level effects on transcriptional regulation, promoter regions, and RNA secondary structure, with PM1, PM3, and PP4 as key supports, and it resolved conflicting ClinVar calls into likely pathogenic or uncertain.

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