SGCD was originally evaluated for DCM by the ClinGen DCM GCEP on 22 November 2019. Evidence of the association of this gene with DCM was re-evaluated using SOP v10 on 30th March 2025. As a result, the classification changed from limited to no known disease relationship. A summary of the information contributing to the classification of this gene at the time of re-evaluation is summarized herein.
SGCD was first reported in relation to autosomal dominant dilated cardiomyopathy in 2000 (Tsubata et al, PMID 10974018). Human genetic evidence supporting this gene-disease relationship includes case-level data. At least 30 variants (20 missense, one splice, one nonsense, two frameshift, three deletion and three intronic polymorphisms) have been reported in humans. Though most of these variants are found too commonly to explain disease. Variants in this gene have been reported in at least 33 probands in 11 publications (Tsubata et al, 2000, PMID: 10974018; Karkkainen et al, 2003, PMID: 14564412; Sylvius et al, 2003, PMID: 12794684; Baydar et al, 2016, PMID: 27488758; Bauer et al, 2009, PMID: 19259135; Chen et al, 2015, PMID: 26720722; Hata et al, 2019, PMID: 31024045, Alimohamed et al, 2023, PMID: 36270459, Shen C. et al. 2022, PMID: 35284542, Escobar-Lopez L. et al. 2021, PMID 34674813, Pugh TJ, et al. 2014, PMID: 24503780). A variant (S151A) in this gene segregated with disease in 2 additional family members. However, the S151A variant occurs too frequently to explain disease and alternative genetic causes of disease in the family were not ruled out. This gene-disease relationship has been studied in at least one case-control study (Mazzarotto et al, 2020, PMID: 31983221) at the aggregate variant level. There was no enrichment of SGCD found in the DCM cohort compared to controls (p=0.74). In addition, this gene-disease association is supported by multiple animal models (pig, hamster, mouse and drosophila), expression studies, and rescue studies in two mouse models. SGCD has also been implicated in autosomal recessive Limb Girdle Muscular Dystrophy (LGMD) which has been assessed separately (definitive, November 14, 2024).
No convincing evidence for a causal role SGCD and AR DCM has been reported. Although this gene-disease assertion is supported by experimental evidence, there is not convincing evidence directly implicating this gene in humans. This classification was approved by the ClinGen Dilated Cardiomyopathy Working Group on 30th March 2025 (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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