HMGCR was first reported in relation to autosomal recessive limb-girdle muscular dystrophy in 2023 (Yogev Y et al., PMID:36745799). At least 10 variants (eight missense, one in-frame deletion and one intronic) have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data, segregation data, and experimental data. Variants in this gene have been reported in at least six probands in two publications (PMID:36745799, PMID:37167966). Variants in this gene segregated with disease in nine additional family members. One large consanguineous kindred is reported with an LOD score of 4.8204 (PMID:36745799). The mechanism for disease is unknown. This gene-disease association is supported by a mouse model recapitulating the human limb-girdle muscular dystrophy phenotype (PMID:26381177). Using skeletal muscle-specific HMGCR knockout mice the authors demonstrated that mice missing HMGCR expression in their skeletal muscle exhibit muscle weakness, exercise intolerance, elevated creatine kinase levels and abnormal/myopathic muscle biopsy. These clinical features are also seen in the human probands included in this curation. In summary, there is moderate evidence to support this gene-disease relationship. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged. This classification was approved by the ClinGen Muscular Dystrophies and Myopathies Gene Curation Expert Panel on the meeting date 13 August 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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