Development of RS1-specific ACMG/AMP variant classification criteria with pilot variant curation

RS1

Gene-specific ACMG/AMP rule specification for RS1: 28 codes across four strength levels spanning phenotype, population, computational, functional and segregation domains

The ClinGen X-Linked Inherited Retinal Diseases Variant Curation Expert Panel adapted ACMG rules to the RS1 gene, in the context of gene therapies for X-linked retinoschisis where distinguishing pathogenic from benign variants governs patient enrolment. The framework, described as highly systematic and conservative, applies 28 codes across four strength levels. Fifty-four pilot variants were tested, 47 of them present in ClinVar. Twenty-one variants were reclassified: two likely pathogenic and one likely benign variant became variants of uncertain significance, and four previously unclassified variants were assigned pathogenic, likely pathogenic or likely benign status. Other changes resolved conflicts or multiple classifications.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

The striking point is the direction of several reclassifications: three variants lose their pathogenic or benign status and revert to uncertain. That is exactly what a conservative framework should produce, and exactly what is needed before enrolling a patient in a gene therapy trial, where an inclusion error is costly. Still, 54 pilot variants cover only a fraction of the RS1 allelic spectrum, so real clinical utility will depend on the pace of curating the rest.

Analysis by Dr Thibaut Benquey