ACBD5 was first reported in relation to autosomal recessive ACBD5 deficiency in 2013 (Abu-Safieh L et al., PMID: 23105016). More than ten pathogenic/likely pathogenic variants have been reported in humans per ClinVar. Evidence supporting this gene-disease relationship includes case-level data and experimental data. Summary of case-level (12 pts) and experimental data (3.5 pts): 15.5 points. Variants in this gene have been reported in at least 5 probands in 5 publications (PMID: 23105016, PMID: 27799409, PMID:33427402, PMID: 37789430, PMID: 34668366). The mechanism for disease is expected to be loss of function. This gene-disease association is supported by in vitro functional assays.
At the time of curation (April 2020), this gene did not have associated disease entities per OMIM, but subsequently "Retinal dystrophy with leukodystrophy" was added as the disease entity. There have been associations with retinal dystrophy (PMID:23105016) and ACBD5 deficiency (PMID:27799409) in the literature. Additionally, there has been a report of an association with autosomal dominant thrombocytopenia (PMID:20626622), but this was later disputed (PMID:21211618). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in molecular mechanism, inheritance pattern, or phenotypic variability among the reports of retinal dystrophy and ACBD5 deficiency. Therefore, all of the disease entities have been lumped into one disease entity, ACBD5 deficiency (MONDO:0100112).
In summary, ACBD5 is definitively associated with ACBD5 deficiency. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.
This gene-disease pair was originally evaluated by the Peroxisomal Disorders GCEP on April 20, 2022 as a moderate classification. It was reevaluated on May 2, 2024. As a result of this reevaluation, the classification was upgraded from Moderate to Definitive.
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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