TPM1

Inheritance Pattern: AD

Disease ID:MONDO:0012744

Submitter: ClinGen

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).

Inheritance Pattern: AD

Disease ID:MONDO:0016587

Submitter: ClinGen

There is no evidence that TMP1 is involved in ARVC. This gene has been investigated for pathogenic variants in a cohort of 137 ARVC patients meeting 2010 Task Force criteria for ARVC (29709087). No variants in TMP1 were reported.

Inheritance Pattern: AD

Disease ID:MONDO:0015470

Submitter: Orphanet

Inheritance Pattern: AD

Disease ID:MONDO:0012744

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AD

Disease ID:MONDO:0007267

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AD

Disease ID:MONDO:0007267

Submitter: G2P

Inheritance Pattern: AD

Disease ID:MONDO:0018901

Submitter: Orphanet

Inheritance Pattern: AD

Disease ID:MONDO:0005045

Submitter: ClinGen

The TPM1 gene has been associated with hypertrophic cardiomyopathy. TPM1 was first associated with this disease in humans in 1994 (Thierfelder et al, PMID 8205619). At least 15 unique heterozygous variants (missense), with varying levels of evidence to support their pathogenicity, have been reported in humans (reviewed in Redwood and Robinson, 2013, PMID 24005378). The c.523G>A (p.Asp175Asn) variant has a MAF of 0.0001250 in the European Finnish population in gnomAD v4, which is above this group's MAF cutoff (0.0001), but the highest continental population frequency is 0.00001098 (South Asian population). This variant has not been given a reduced score since there is a potential founder effect in the Finnish population and the highest continental population frequency is below the group's MAF cutoff. Variants in this gene segregated with disease in at least 7 families (Thierfelder et al, 1994, PMID 8205619; Jääskeläinen et al, 1998, PMID 9822100; Karibe et al, 2001, PMID 11136687; Jongbloed et al, 2003, PMID 12651045). The mechanism for disease is likely dominant negative (Redwood and Robinson, 2013, PMID 24005378). The gene-disease relationship is supported by the function of the gene product, animal models, and in vitro assays. In summary, TMP1 is definitively associated with hypertrophic cardiomyopathy. This has been repeatedly demonstrated in both research and clinical diagnostic settings, and has been upheld over time. This classification was originally approved by the ClinGen Hypertrophic Cardiomyopathy Gene Curation Committee, subgroup of the ClinGen Cardiovascular Working Group, on December 20, 2016 using SOP version 5. It was reevaluated on July 13, 2021. As a result of this re-evaluation, the classification did not change. A precuration was performed December 18, 2023 to evaluate whether HCM should be curated alone or with other cardiac phenotypes. The HCVD GCEP decided that HCM should be curated alone and there was no need to recurate for this disease entity since it has a definitive relationship with TPM1, but the scoring was updated using SOP version 10.