Clinical Domain Working Groups

The Galactosemia Variant Curation Expert Panel plans to curate, in the order of clinical importance, the variants of four galactosemia-associated genes with a “strong” or “definitive” gene disease validity, starting with GALT. The Inborn Errors of Metabolism Gene Curation Expert Panel (IEM GCEP) curated GALE, GALK1, and GALT to have a “definitive” gene disease validity, and GALM to have a “strong” gene disease validity. Current members of the expert panel are experienced in different aspects of galactosemia and inborn errors of metabolism, including direct patient care, biochemical and molecular laboratory interpretation and testing, and variant classification/curation.

Variant interpretation criteria will be adapted and specified for each gene, particularly PVS1, PM3, PS2, PS3, PM2, BA1, BS1, PP3/BP4, PM5 and PP4, similarly to prior variant curation procedures for inborn errors of metabolism genes. A curation SOP will be created for standardization and the ClinGen Variant Curation Interface (VCI) will be used to document evidence used for variant classification.

Variants in the selected genes will be collected from the Human Gene Mutation Database (HGMD -http://www.hgmd.cf.ac.uk/), ARUP Galactosemia database (PMID 17486650), GalNet (PMID 27837294), and Leiden Open Variation Database (LVOD -http://www.lovd.nl/3.0/home) and ClinVar. Additional variants are expected to be identified by the VCEP members by other means as well, including (but not limited to) existing molecular testing laboratories and metabolic clinics/clinicians. To date, ClinVar lists approximately 880 variants in the GALT gene, 977 variants in the GALK1 gene, 382 variants in the GALE gene, and 109 variants in the GALM gene (accessed: 10/2/2024).