Submission Details

PLEKHM1 is located at chromosome 17q21.31, has 12 exons, 1056 amino acids. It encodes a protein that is required in the late endosomal/lysosomal vesicles and bone resorption. Multiple disease entities have been reported in association with this gene. According to criteria outlined by the ClinGen Lumping and Splitting Working Group, there was evidence of differences in their molecular mechanism and phenotypic spectrum. Therefore, the following disease entities have been split into multiple disease entities: autosomal dominant osteopetrosis 3 (MONDO:0020848). PLEKHM1 was first reported in relation to autosomal dominant osteopetrosis 3 in 2008). Two unique variants(1 missense, 1 frameshift) reported in two publications have been included in this curation (PMID: 17997709, 27291868). An additional proband harboring a variant in exon 7 of the PLEKHM1 gene variant has been reported, although the precise nature of this variant is concealed (PMID: 21054159). A total of 2.5 genetic evidence points was reached without experimental evidence. In summary, there is limited evidence supporting the relationship between PLEKHM1 and AD osteopetrosis 3. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease relationship. This classification was approved by the ClinGen Skeletal Disorders GCEP on the meeting date (03/06/24) (SOP Version 10).