The BMP6 gene was first reported in relation to susceptibility to iron overload in 2006 (Babitt JL et al., PMID: 19252488), showing that BMP6 upregulates hepatocyte hepcidin expression—a process enhanced by hemojuvelin and blunted in* Hfe2*−/− hepatocytes. Per the criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in molecular mechanism and inheritance pattern.Six missense variants, with at least six probands reported in association with iron overload across six publications (PMID: 26582087, PMID: 28335084, PMID: 29695288, PMID: 27590690, PMID: 34037557, PMID: 38719717), were evaluated but not included due to high allele frequency in healthy populations (gnomAD v4.1).One missense variant, c.1180G>A (p.Val394Met), with additional in vitro assay data showing a three-fold reduction in hepcidin induction by the mutant compared to wild-type BMP6, was included in this curation (PMID: 34037557). The mechanism of pathogenicity appears to be loss of function.This gene-disease relationship is also supported by animal models showing accumulation of iron in the liver, the acinar cells of the exocrine pancreas, the heart, and the renal convoluted tubules (PMID: 19252488; PMID: 19252486), as well as expression studies showing *Bmp6 *expression induced by dietary iron content (PMID: 18539898). In summary, there is limited evidence supporting the relationship between BMP6 and susceptibility to iron overload. This classification was approved by the ClinGen IEM GCEP at the meeting on May 9, 2025 (SOP Version 11).
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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