rs193922680 — ACTC1 ACTC1 p.Glu101Lys

Pathogenic missense variant in cardiac alpha-actin that causes hypertrophic cardiomyopathy, left ventricular noncompaction, and septal defects through impaired sarcomeric force generation.

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The Cardiac Actin Variant That Hides in the Apex

Cardiac alpha-actin is the molecular backbone of every heartbeat. Encoded by the ACTC1 gene, it polymerizes into thin filaments that interdigitate with myosin heavy chains to generate the force your heart needs to eject blood. The p.Glu101Lys variant — a single amino acid substitution at position 101 of this actin — disrupts the mechanical handshake between actin and myosin in a way that forces the heart to compensate, sometimes silently for decades.

This is a rare but high-impact pathogenic variant. ClinVar classifies it as Pathogenic with 4-star expert panel review11 4-star expert panel review
ClinGen Cardiomyopathy Variant Curation Expert Panel, November 2025, the highest confidence level ClinVar assigns.

The Mechanism

Glutamic acid at position 10122 Glutamic acid at position 101
a negatively charged amino acid in subdomain 1 of actin sits directly adjacent to the myosin head binding interface. Substituting the negatively charged glutamate with the positively charged lysine (E101K) disrupts this electrostatic environment and reduces myosin binding affinity. In vitro studies show the mutation produces slower actin-myosin sliding velocity, reduced force generation, and a weaker actomyosin interaction in the presence of ATP.

The net effect is a compensatory increase in myofibrillar calcium sensitivity — the heart tries to squeeze more contractile force from each calcium transient. This hypersensitivity to calcium is mechanistically linked to the resulting hypertrophy, particularly concentrated at the cardiac apex33 cardiac apex
the pointed tip of the left ventricle, frequently the last region affected in typical HCM. A transgenic mouse model expressing the closely related E99K mutation reproduced apical hypertrophy with increased interstitial fibrosis and sarcomere disarray, and showed a 2.3-fold increase in calcium sensitivity in reconstituted thin filaments.

The Evidence

The landmark family study by Monserrat et al. (2007)44 Monserrat et al. (2007)
Mutation in the alpha-cardiac actin gene associated with apical HCM, LVNC, and septal defects. Eur Heart J, 2007 screened 247 HCM/LVNC families and found ACTC1 E101K in 5 probands. Among 46 mutation-positive family members, 22 met criteria for apical hypertrophic cardiomyopathy, 23 fulfilled criteria for left ventricular noncompaction (LVNC), and 9 had atrial or ventricular septal defects. Five premature sudden cardiac deaths and one heart transplant were documented among carriers.

Arad et al. (2005)55 Arad et al. (2005)
Gene mutations in apical hypertrophic cardiomyopathy. Circulation, 2005 identified E101K in two families and noted that all 16 affected members showed exclusively apical hypertrophy — a remarkably consistent phenotype rarely seen with other sarcomere gene mutations.

The 2024 AHA/ACC HCM guideline 66 Ommen et al. Circulation, 2024 endorses ACTC1 as a definitive HCM gene requiring cascade screening, periodic echocardiographic surveillance, and risk stratification for sudden cardiac death in gene-positive individuals.

A 2025 case series 77 Zarate et al. Clin Genet, 2025 expanded the phenotypic spectrum further, noting that ACTC1 Glu101 variants can present with extracardiac features including facial dysmorphism and skeletal anomalies in some kindreds, widening the clinical picture beyond isolated cardiomyopathy.

Practical Actions

Carriers of the T allele require structured cardiac surveillance regardless of symptoms. Apical HCM is frequently missed on standard echocardiography if the apex is not specifically evaluated; contrast echocardiography or cardiac MRI can improve detection. LVNC overlap phenotypes require attention to trabeculation depth and left ventricular systolic function.

The 2024 AHA/ACC guidelines recommend echocardiography every 1-2 years for gene-positive children and every 3-5 years for asymptomatic gene-positive adults. Cardiology review should be prompted immediately if symptoms develop (palpitations, exertional dyspnoea, syncope, chest pain) or if echocardiographic surveillance shows new wall thickening, systolic dysfunction, or increased LV trabeculation.

Sudden cardiac death risk stratification (using the HCM Risk-SCD calculator or equivalent) should be performed by a cardiologist with HCM expertise; ICD implantation may be recommended for carriers with additional risk features (maximum wall thickness ≥30 mm, non-sustained VT, unexplained syncope, family history of SCD, or abnormal blood pressure response to exercise).

Cascade genetic testing of first-degree relatives (parents, siblings, children) should be offered. Each first-degree relative has a 50% probability of inheriting the variant. Variant-negative relatives can be discharged from cardiac surveillance; variant-positive relatives enter the surveillance programme regardless of echocardiographic findings at baseline.

Interactions

ACTC1 E101K acts through the sarcomere, the same final effector pathway as MYH7, MYBPC3, TNNT2, TNNI3, TPM1, and MYL2 mutations. Individuals who carry two sarcomere gene mutations (digenic disease) generally present with earlier onset and more severe phenotypes. If a variant is found in ACTC1, genetic panels should evaluate for concurrent mutations in other sarcomere genes. Compound sarcomere mutation carriers warrant accelerated surveillance and lower thresholds for ICD consideration. No specific ACTC1 E101K gene-drug interactions affecting cardiac drug efficacy have been identified.

Genotype Interpretations

What each possible genotype means for this variant.

CC Non-Carrier Normal

No pathogenic ACTC1 variant detected

You carry two copies of the common reference allele at this position in the ACTC1 gene. You do not carry the p.Glu101Lys pathogenic variant associated with hypertrophic cardiomyopathy and left ventricular noncompaction. This variant is present in fewer than 1 in 70,000 alleles in the general population (gnomAD genomes), so the common result by a wide margin is no pathogenic change at this position.

CT Pathogenic Carrier High Risk

Carries one copy of the ACTC1 p.Glu101Lys pathogenic variant

The Glu101Lys substitution replaces a negatively charged glutamic acid with a positively charged lysine at a position directly adjacent to the myosin head binding interface of cardiac alpha-actin. This disrupts the electrostatic environment at the actomyosin junction, reducing myosin binding affinity and force output. The sarcomere compensates by upregulating calcium sensitivity, which over time drives pathological hypertrophy — predominantly at the cardiac apex, giving rise to the distinctive apical HCM phenotype.

The phenotypic spectrum is broad. In one large family study (Monserrat et al. 2007), 22 of 46 carriers had apical HCM, 23 had LVNC (which can overlap substantially with apical HCM on imaging), and 9 had septal defects. One individual required a heart transplant; five died prematurely from sudden cardiac death. Sudden death risk was highest in carriers with greater wall thickening or systolic dysfunction. A minority of carriers have extracardiac features (dysmorphism, short stature, skeletal anomalies) based on more recent case reports.

Because this is an autosomal dominant variant, each biological child of a carrier has a 50% probability of inheriting it. Cascade testing of all first-degree relatives is the standard of care.

TT Homozygous (Extremely Rare) High Risk

Carries two copies of the ACTC1 p.Glu101Lys pathogenic variant — an extremely rare genotype

No homozygous carriers of ACTC1 E101K have been reported in the scientific literature. In dominant sarcomere diseases where homozygotes have been identified (e.g. MYH7 or MYBPC3 compound heterozygotes), the phenotype is consistently more severe — often presenting in infancy or childhood with restrictive or severely hypertrophic physiology requiring early transplantation. The absence of homozygotes in gnomAD despite large sample sizes is consistent with a reduction in reproductive fitness or embryonic lethality in the TT state.

If this result was obtained from a consumer genotyping chip (23andMe, AncestryDNA, etc.), a false-positive is plausible for ultra-rare pathogenic variants at low-depth coverage. Confirmatory clinical-grade sequencing (Sanger or WGS) is strongly indicated before acting on this result.