TPM1 was originally evaluated for DCM by the ClinGen DCM GCEP on 08/24/2020. Evidence of the association of this gene with DCM was re-evaluated using SOP v10 on 04/04/2025. As a result, the classification did not change. A summary of the information contributing to the classification of this gene at the time of re-evaluation is summarized herein.
Variants in TPM1 were first reported in relation to autosomal dominant dilated cardiomyopathy (DCM) in 2001 by Olson et al (2001, PMID: 11273725). At least nine unique missense variants have been reported in the literature in individuals clinically diagnosed with DCM. Human evidence supporting this gene-disease relationship includes case-level data, segregation data, and case-control data. Extensive segregation with disease has been demonstrated in several unrelated families, including six affected individuals described by Van der Meerakker et al (2013, PMID: 23147248) and 16 affected individuals across two unrelated families described by Lakdawala et al (2010, PMID: 20117437). An aggregate case-control study has shown significant enrichment of rare non-truncating TPM1 variants in DCM patients vs controls, with variants occurring significantly more than expected in pediatric cases (Mazzarotto et al, 2020, PMID: 31983221). During the re-curation process, genetic evidences from most of the previous studies were not scored since genetic testing was based on single-gene analysis and relevant DCM related genes (i.e. TTN and FLNC) were not included.
Since 2022, 3 different missense variants have been reported in DCM patients (Man et al. PMID 35029218, Zaklyazminskaya et al. PMID 39684770, Barrick et al. PMID 3673994), two of which were de novo.
The gene-disease association is also supported by an animal (mouse) model (Lynn et al, 2017, PMID: 28600229), and several in-vitro functional assays (Gupte et al, 2015, PMID: 25548289; Van der Meerakker et al, 2013, PMID: 23147248; Lakdawala et al, 2010, PMID: 20117437; Kopylova et al, 2019, PMID: 31643006). The mechanism of disease appears to be dominant loss of function. Conceptually, the hypothesis is that DCM-linked α-Tm mutations decrease force generation and lead to a primary dilation of the left ventricle (Stefanelli, 2004, PMID: 16043485).
In summary, there is moderate evidence supporting the relationship between TPM1 and DCM. This classification was approved by the ClinGen Dilated Cardiomyopathy Working Group on 04/04/2025 (SOP Version 10).
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