TRIM63

Inheritance Pattern: AR

Disease ID:MONDO:0005045

Submitter: ClinGen

*TRIM63* was first reported in relation to autosomal recessive hypertrophic cardiomyopathy (HCM) in humans in 2015, where a homozygous truncating variant (p.Q247X) was identified in a single proband whose phenotype included HCM and skeletal myopathy (Olivé et al, PMID 25801283). The *TRIM63* gene encodes an E3 ubiquitin ligase and is part of the ubiquitin-proteasome system, which targets cellular proteins, including sarcomeric proteins, for degradation. *TRIM63* has been associated with autosomal recessive (AR) HCM in 32 probands across 5 publications; the Q247X variant is a recurrent variant reported in 11 of these 32 probands in either a homozygous or compound heterozygous state (Olivé et al, 2015, PMID 25801283; Jokela et al, 2019, PMID 30372688; Salazar-Mendiguchía J et al, 2020, PMID 32451364; Andreeva et al, 2022, PMID 35273634; Allouba M, et al., 2023, PMID: 37431535); however, the Q247X variant has limited functional evidence for disease causation. Case-control evidence showed enrichment of biallelic TRIM63 variants in cases compared to controls, but this study did not calculate or report statistical significance (Salazar-Mendiguchía J et al, 2020, PMID 32451364). Importantly, there have been at least 2 reports of co-occurring HCM and skeletal myopathy in the presence of biallelic *TRIM63* variants (Olivé et al, 2015, PMID 25801283; Jokela et al, 2019, PMID 30372688). One of the described probands was also found to have a heterozygous TRIM54 variant. This raises the possibility of a broader phenotype including skeletal myopathy, but more evidence is needed. This gene-disease relationship is also supported by expression studies (Bodine et al, 2001, PMID 11679633; Fagerberg et al, 2014, PMID 24309898), protein interaction with TNNI3, MYBPC3, TNNT2, and MYH7 (Kedar et al, 2004, PMID 15601779, Mearini et al, 2010, PMID 19850579, Witt et al, 2005, PMID 15967462, Fielitz et al, 2007, PMID 17786241), biochemical function (Kedar et al, 2004, PMID 15601779, Mearini et al, 2010, PMID 19850579, Arya et al, 2004, PMID 15596539), and a model system (Willis et al, 2007, PMID 17272810). In summary, the evidence supporting the relationship between TRIM63 and autosomal recessive HCM is moderate. This classification was approved by the ClinGen Hereditary Cardiovascular Diseases GCEP on June 6, 2024.

Inheritance Pattern: AD

Disease ID:MONDO:0024573

Submitter: G2P

Inheritance Pattern: AD

Disease ID:MONDO:0005045

Submitter: ClinGen

The TRIM63 gene encodes an E3 ubiquitin ligase and is part of the ubiquitin-proteasome system, which targets cellular proteins, including sarcomeric proteins, for degradation. TRIM63 was first reported in relation to autosomal dominant hypertrophic cardiomyopathy in 2012 (Chen et al, 2012, PMID 22821932) and has been reported in no subsequent clinical reports, though evidence for autosomal recessive disease is emerging. The split curation for autosomal recessive inheritance has been curated separately. Chen et al. reported 3 variants in 5 probands, including 2 missense variants in 3 probands, and one truncating variant (p.Q247X) in 2 probands without segregation. The p.Q247X variant has an allele frequency of 0.0007 (0.008 in the Ashkenazi Jewish population), considered too high for AD inheritance. All 3 variants have limited functional evidence for disease causation. A case control study utilizing aggregate variant analysis reported rare variants in TRIM63 at a higher frequency in cases compared to controls (Su et al, 2014, PMID 24865491). A second case control study (Walsh et al, 2017, PMID 27532257) found no enrichment of rare variants in cases vs. controls. Notably, multiple reports of AR inheritance have demonstrated no disease in heterozygote relatives (Olive et al, 2015, PMID 25801283, Andreeva et al, 2022, PMID 35273634, Salazar-Mendiguchia et al, 2020, PMID 32451364). This gene-disease association is supported by expression studies (Bodine et al, 2001, PMID 11679633; Fagerberg et al, 2014, PMID 24309898), protein interaction with TNNI3, MYBPC3, TNNT2, and MYH7 (Kedar et al, 2004, PMID 15601779, Mearini et al, 2010, PMID 19850579, Witt et al, 2005, PMID 15967462, Fielitz et al, 2007, PMID 17786241), and biochemical function (Kedar et al, 2004, PMID 15601779, Mearini et al, 2010, PMID 19850579, Arya et al, 2004, PMID 15596539). The original curation was published on December 20th, 2016 with a classification of Limited. At the time of this re-curation, no new genetic level evidence has emerged to support the disease mode of inheritance. In summary, the evidence supporting the relationship between TRIM63 and autosomal dominant HCM has been disputed, and no valid evidence remains to support the claim. More evidence is needed to either support or entirely refute the role TRIM63 plays in this disease. This classification was approved by the ClinGen Hypertrophic Cardiomyopathy Gene Curation Expert Panel on October 27th, 2022.

Inheritance Pattern: AR

Disease ID:MONDO:0005045

Submitter: Ambry Genetics

Inheritance Pattern: AR

Disease ID:MONDO:0005045

Submitter: PanelApp Australia