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.
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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