TCIRG1 was first reported in relation to autosomal recessive Osteopetrosis 1 in 2000 (Frattini et al., PMID:10888887). Osteopetrosis is caused by subnormal osteoclast function that typically manifests in the first few months of life. It is characterized by: abnormally dense bone, macrocephaly and frontal bossing, tooth defects, feeding difficulties, visual and hearing loss, bone marrow insufficiency, severe anemia, and hepatosplenomegaly. At the time of this curation, there were no other single-gene disorders associated with this gene. This curation is based on this disease entity only. 24 variants (missense, splice site, frameshift, nonsense) that have been reported in 12 probands in three publications (PMIDs: 11532986, 10888887, 34545712) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity appears to be loss of function. This gene-disease association is also supported by animal models, expression studies, and functional alteration studies (PMIDs:10888887,19448635,11532986, 10709991). In summary, TCIRG1 is definitively associated with autosomal recessive Osteopetrosis 1. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.This classification was approved by the ClinGen Skeletal Disorders GCEP on the meeting date 03/01/23 (SOP Version 9).
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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