PLEKHM2 (pleckstrin homology domain-containing family M member 2) was originally evaluated for DCM by the ClinGen DCM GCEP on 10/09/2020. Evidence of the association of this gene with DCM was re-evaluated using SOP v10 on 11/15/2025. As a result, the classification changed. A summary of the information contributing to the classification of this gene at the time of re-evaluation is summarized herein. Human genetic evidence supporting this gene-disease relationship includes three case-level data. At least three variants were reported in association with human DCM. PLEKHM2 c.1932_1933delGA (p.Lys645Alafs12) was reported in relation to autosomal recessive dilated cardiomyopathy (DCM) in a large consanguineous Bedouin family in the homozygous state in three related individuals (Muhammad et al., 2015, PMID 26464484). The role of this protein is primarily related to lysosomal trafficking (Rosa-Ferreira & Munro, 2011, PMID 22172677; Khatter et al., 2015, PMID 25908847; Almacellas et al., 2020, PMID 32573315). The authors of this case-level and segregation data also present experimental evidence supporting this gene-disease assertion, including expression studies using western blot which demonstrated that the PLEKHM2 protein is expressed in fibroblasts of two of the relatives with DCM from the aforementioned pedigree. The patient-derived iPSC-cardiomyocytes showed low expression levels of genes encoding contractile functional proteins (Korover et al., 2023, PMID: 37349842). PLEKHM2 c.2756del (p.Gly919Ala_fs34) and c.1986G>A (p.Ser662Ser=) were found in a 21-year-old Caucasian patient in compound heterozygous state (trans). The Westen blot using the patient’s heart did not express PLEKHM2 protein. PLEKHM2 c.2923-2A>G was found in an individual with DCM (Helio et al., 2023, PMID: 37795486). However, the pathogenicity of this variant remains unclear. In summary, there is moderate evidence to support this gene-disease relationship. More evidence is needed to establish the relationship of PLEKHM2 with AR DCM definitively. This classification was approved by the ClinGen Dilated Cardiomyopathy Working Group on 11/15/2024 (SOP Version 10).
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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