rs104894503 — TPM1 D175N (Asp175Asn)

TPM1 D175N — When the Cardiac Contraction Switch Stays Open

The heart's ability to pump depends on a precisely timed molecular switch inside every muscle fiber. Tropomyosin¹¹ Tropomyosin
A coiled-coil protein that winds along actin filaments in the sarcomere, blocking or exposing myosin binding sites in response to calcium signals sits at the center of this switch. In the resting heart, tropomyosin physically blocks myosin from grabbing actin. When calcium floods in during a heartbeat, tropomyosin pivots, exposing binding sites and triggering contraction. The TPM1 D175N variant — a single amino acid swap at position 175 of the alpha-1 chain — shifts this pivot point toward the "open" position even when calcium is still low, causing the heart to contract too readily, too forcefully, and eventually to remodel in dangerous ways.

The Mechanism

TPM1 encodes the alpha-tropomyosin chain²² alpha-tropomyosin chain
One of the two major sarcomeric tropomyosin isoforms; TPM1 is the cardiac-dominant form while TPM2 predominates in slow skeletal muscle, the primary regulatory component of the cardiac thin filament. At position 175, the normal aspartate residue (D) forms ionic interactions that hold tropomyosin in the blocked conformation at low calcium. The D175N substitution (G>A on chromosome 15, GRCh38: chr15:63060899) replaces this negatively charged aspartate with the neutral asparagine, weakening the restraint on tropomyosin's movement.

The result, demonstrated directly by Borovikov et al. using fluorescence-labeled thin filaments³³ Borovikov et al. using fluorescence-labeled thin filaments
The team incorporated Asp175Asn tropomyosin into isolated muscle fibers and tracked positional changes during the ATPase cycle, is that D175N tropomyosin stays shifted toward the open state throughout the contraction cycle, increasing the affinity of myosin for actin and allowing more cross-bridges to attach at any given calcium concentration. Calcium sensitivity of the thin filament rises — the heart contracts harder per unit of calcium signal. Over years, hypercontractility drives hypertrophic remodeling⁴⁴ hypertrophic remodeling
Asymmetric thickening of the left ventricular wall, particularly the interventricular septum, the cardinal anatomical feature of HCM, diastolic dysfunction, and eventually outflow tract obstruction or arrhythmia.

The Evidence

D175N is one of the best-characterized pathogenic tropomyosin variants in cardiology. It was classified by ClinVar as Pathogenic with a two-star review ("criteria provided, multiple submitters, no conflicts") across 22 submitting laboratories, including GeneDx, Blueprint Genetics, Invitae, and Color Diagnostics.

In Finland, D175N is a founder mutation⁵⁵ founder mutation
A variant that entered a population from a small number of ancestors and is now found at higher frequency than the global average due to population expansion from a bottleneck with geographic clustering in central and western Finland. Jääskeläinen et al. (2013)⁶⁶ Jääskeläinen et al. (2013)
Screening of 306 unrelated Finnish HCM patients from a catchment area of ~4 million people identified D175N in 6.5% of cases; an earlier regional study found it in 11% of HCM patients in eastern Finland, where it accounted for a substantial fraction of all diagnoses alongside five other founder mutations.

Imaging studies demonstrate the functional impact directly. Sipola et al. (Radiology, 2005)⁷⁷ Sipola et al. (Radiology, 2005)
Cine MRI in 24 D175N carriers vs 17 healthy controls, mean age 42 found that the proportion of hypokinetic myocardial segments was 37% in carriers versus 12% in controls (p < 0.001), and that the severity of contractile impairment independently predicted both LV mass (R² = 0.42) and maximal wall thickness (R² = 0.48). More recent genotype-outcome data from Conde et al. (2025)⁸⁸ Conde et al. (2025)
Retrospective cohort of 77 genotyped HCM patients with cardiac MRI, collected 2018–2024 found that thin filament variants — the class that includes TPM1 D175N — were associated with an 80% rate of non-sustained ventricular tachycardia and a 4.4-fold increased risk of major adverse cardiovascular events compared to mutation-negative HCM.

The nationwide FinHCM study (2019)⁹⁹ FinHCM study (2019)
382 unrelated index patients, 482 total participants including relatives, followed longitudinally found annual all-cause mortality of 1.70% among HCM patients carrying sarcomere mutations, roughly double the 0.87% rate in matched general population. Sudden cardiac death events were rare (n=8) but independent risk factors included greater LV wall thickness and systolic dysfunction.

Practical Actions

Because D175N acts in an autosomal dominant fashion, a single copy is sufficient to cause disease. Approximately 50% of first-degree relatives of an affected individual will carry the variant. Cascade genetic testing of all first-degree relatives (parents, siblings, children) is the cornerstone of management — relatives who test negative require no further cardiac surveillance for this variant, while those who test positive enter a monitoring program.

For carriers, management follows ESC and ACC/AHA hypertrophic cardiomyopathy guidelines¹⁰¹⁰ ESC and ACC/AHA hypertrophic cardiomyopathy guidelines
European Society of Cardiology 2023 HCM guidelines and ACC/AHA 2020 guidelines. Annual or biennial echocardiography and periodic Holter monitoring are standard. ICD implantation decisions are individualized using a formal SCD risk calculator (ESC HCM Risk-SCD score, which considers LV thickness, family SCD history, unexplained syncope, non-sustained VT, and LV outflow gradient). The phenotype in D175N carriers spans from subclinical hypertrophy to significant obstruction and arrhythmia, making serial monitoring essential.

Early-stage carriers may show the hypermetabolic compensatory state documented by PET imaging before overt hypertrophy emerges. This window represents an opportunity to establish specialist follow-up and baseline imaging before structural changes progress.

Interactions

HCM caused by D175N follows the "final common pathway" hypothesis: multiple sarcomere gene variants converge on the same phenotype via different mechanisms. Compound or double heterozygosity — carrying D175N alongside a pathogenic variant in MYH7 (beta-myosin heavy chain), MYBPC3 (cardiac myosin-binding protein C), or other sarcomere genes — is documented in individual cases and generally associated with more severe, earlier-onset disease. The FinHCM cohort included patients with multiple pathogenic sarcomere variants who showed accelerated hypertrophy and higher SCD risk. When cascade testing reveals that a family member carries both D175N and a second sarcomere variant, subspecialist referral for intensified surveillance is warranted.