Submission Details

The relationship between TCAP and autosomal recessive limb girdle muscular dystrophy (type 2G included), has been evaluated using the ClinGen Clinical Validity Framework as of August, 2021. This association was made using case-level, segregation, and experimental data. The TCAP gene is located on chromosome 17q12. The transcript referred to in the literature (NM_003673.3) is 960 bp long with 2 exons encoding a 167-amino acid protein. More than 20 pathogenic and likely pathogenic variants reported in humans with autosomal recessive limb girdle muscular dystrophy (AR-LGMD) are recorded in ClinVar, most of them being predicted loss of function variants such as nonsense, frameshift, deletion/duplication and splicing variants. Since the gene has only 2 exons, most predicted loss of function variants do not cause nonsense-mediated mRNA decay. Patients with AR-LGMD due to TCAP variants show progressive proximal muscle weakness (along with distal weakness in some) with an average age at onset in the second decade, difficulty in walking and running with loss of ambulation in some, foot drop, increased serum creatine kinase levels, and a muscle biopsy showing dystrophic changes. TCAP has been reported in association with AR-LGMD as early as 2000 by Moreira et al (PMID: 10655062).

Summary of Case Level Data (12 points): The association is seen in at least 7 probands in 4 publications (PMIDs: 10655062, 28666572, 27618135, 25055047). Variants in the gene segregated with disease in 11 additional family members. More case-level evidence is available in the literature, but the maximum score for genetic evidence (12 pts) has been reached.

The mechanism for disease is expected to be biallelic loss of function.

Summary of Experimental Data (3.5 points): This gene-disease relationship is supported by animal models, expression studies, and protein interaction assays. TCAP encodes the telethonin protein that localizes to the Z-disk in the sarcomere and interacts with titin to form the titin cap, which is essential for sarcomere formation and integrity (PMID: 9645487). Telethonin is expressed in the striated muscles, including the heart and skeletal muscles (PMID: 9817758). The effects of TCAP knockdown are studied in zebrafish models (PMID: 19679566), and the effects of TCAP knockout are studied in mouse models (PMIDs: 20233748, 21799151). Studies show loss of swimming ability in fish and balancing ability on rotating road in mice, as well as muscle histological changes similar to human patients with AR-LGMD due to TCAP variants.

In summary, this gene-disease relationship is definitive. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.

OMIM entities: Hypertrophic cardiomyopathy 25; autosomal recessive limb girdle muscular dystrophy 7.

Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found significant difference in phenotype AND inheritance pattern AND in the absence of a well-defined molecular mechanism in the above-mentioned disease entities. Therefore, the two disease entities may be split and curated separately.