TTR rs113058577 (V122I): Risk and Amyloid Cardiomyopathy
The rs113058577 variant (frequently referenced in clinical literature as V122I or p.Val142Ile) is a missense alteration in the TTR gene. It leads to the production of an unstable transthyretin protein that can aggregate into amyloid fibrils, accumulating in organs such as the heart and peripheral nerves. Carrying this variant is statistically linked to hereditary transthyretin amyloid cardiomyopathy (ATTR-CM) and related conditions, particularly in individuals of African ancestry.
What each genotype means
| Genotype | What the research suggests | Reading |
|---|---|---|
| GG | The individual carries two copies of the common wild-type reference allele. This genotype is not associated with hereditary V122I transthyretin amyloidosis, though age-related (wild-type) amyloidosis remains possible late in life. | Informational |
| GA | The individual is heterozygous, carrying one normal copy and one amyloidogenic V122I (p.Val142Ile) allele. This status is associated with an elevated risk of late-onset hereditary transthyretin cardiomyopathy and carpal tunnel syndrome due to incomplete penetrance. | Higher attention |
| AA | The individual is homozygous for the pathogenic alternative allele, carrying two copies of the V122I variant. While relatively rare, having two copies significantly elevates the likelihood of transthyretin protein misfolding and amyloid deposition. | Higher attention |
Genetic Architecture and Variant Nomenclature
The rs113058577 variant represents a single nucleotide transition located within exon 5 of the TTR gene on chromosome 18q12.1. In standard genomic coordinate systems, it is designated as c.424G>A, resulting in the substitution of valine with isoleucine. In contemporary protein nomenclature adhering to HGVS standards, this is termed p.Val142Ile to account for the inclusion of the 20-amino-acid signal peptide. However, historic and clinical cardiology literature often references this exact change as V122I based on the numbering of the mature secreted protein. In dbSNP records, this loci is closely related to cataloged identifier rs76992529. The alteration replaces a conserved, hydrophobic amino acid, thereby destabilizing the native homotetrameric quaternary structure of the circulating transthyretin complex.
Biological Function of the TTR Gene
The TTR gene provides instructions for producing transthyretin, a serum transport protein synthesized predominantly by the liver, as well as the choroid plexus of the brain and the retinal pigment epithelium. Transthyretin normally circulates as a stable four-subunit tetramer tasked with carrying thyroxine (vitamin hormone T4) and retinol (vitamin A, via retinol-binding protein) throughout the bloodstream. When a missense mutation like V122I is present, the rate-limiting dissociation of the tetramer into monomeric intermediates is accelerated. These misfolded monomers subsequently self-assemble into insoluble, cross-beta sheet amyloid fibrils. As these fibrils aggregate within the extracellular matrix of heart muscle tissue, they disrupt mechanical function and structural compliance, ultimately impeding cardiac relaxation and filling.
Clinical Associations and Strength of Evidence
Extensive biomedical research published in journals such as the [New England Journal of Medicine](https://www.nejm.org/doi/full/10.1056/NEJMoa1404852) and the [Journal of the American College of Cardiology](https://www.jacc.org/doi/10.1016/j.jacc.2020.04.074) confirms that rs113058577 is a major causal factor in late-onset hereditary transthyretin amyloid cardiomyopathy (ATTR-CM). Affected carriers frequently experience late-onset congestive heart failure, restrictive cardiomyopathy, and conduction abnormalities, typically developing in their 60s, 70s, or 80s. Emerging multi-biobank investigations published in [Scientific Reports](https://www.nature.com/articles/s41598-021-91113-6) also demonstrate robust associations with polyneuropathy and preceding carpal tunnel syndrome, the latter often manifesting 5 to 10 years before cardiac diagnosis. Despite the strong association, clinical penetrance is incomplete, meaning not all carriers will develop symptomatic amyloidosis during their lifetime.
Ancestry and Population Frequency
Epidemiological evaluations, including multi-cohort analyses published in [Amyloid](https://www.tandfonline.com/doi/full/10.3109/13506129.2015.1051219) and [Frontiers in Cardiovascular Medicine](https://pmc.ncbi.nlm.nih.gov/articles/PMC9360589/), show that the V122I allele is primarily carried by individuals of West African ancestry. Approximately 3% to 4% of African American individuals carry at least one copy of the variant (an allele frequency of roughly 0.017 to 0.020). By contrast, it is exceptionally rare among populations of European, East Asian, and Indigenous American ancestry without recent African admixture. Because this variant is carried by an estimated 1.5 to 1.6 million individuals in the United States alone, yet has historically faced low clinical detection rates, researchers highlight it as an important target for reducing underdiagnosis and health disparities in cardiovascular care.
Navigating Genetic Results Responsibly
Discovering an rs113058577 risk allele on a consumer or research genetic test does not constitute a clinical diagnosis of cardiac amyloidosis. Because clinical penetrance is variable, possessing the variant indicates potential predisposition rather than guaranteed illness. Clinical evaluations generally require specialized noninvasive screening—such as technetium-99m-pyrophosphate (PYP) nuclear scintigraphy, cardiac MRI, biomarker evaluation, or echocardiography—guided by a cardiologist or medical geneticist. Any discussion regarding medical diagnostics, cardiac symptom monitoring, or pharmacotherapy targeting transthyretin tetramer stabilization should always be conducted in consultation with a qualified physician or genetic counselor.
How common is this variant?
The variant is carried by approximately 3% to 4% of individuals of African American and West African descent, with an allele frequency of roughly 0.017 to 0.020, while remaining extremely rare in other global ancestries.
Frequently asked questions
What is the difference between V122I and p.Val142Ile?
They are two names for the exact same genetic change in the TTR gene. V122I is the historical name derived from the mature, processed protein, whereas p.Val142Ile is the modern HGVS nomenclature counting the 20-amino-acid signal peptide sequence.
Does carrying the rs113058577 variant mean I will definitely develop heart failure?
No. The variant displays incomplete penetrance, meaning that while it increases your statistical risk, a significant proportion of carriers live without ever developing clinical cardiac amyloidosis. Regular monitoring with a healthcare professional can help track cardiac health as one ages.
Why is carpal tunnel syndrome often mentioned with this mutation?
Insoluble transthyretin amyloid fibrils frequently accumulate in musculoskeletal soft tissues long before significant cardiac symptoms emerge. Bilateral carpal tunnel syndrome often precedes the clinical diagnosis of cardiac amyloidosis by 5 to 10 years, serving as a recognized early warning sign.
What should I do if my genetic test shows I am a carrier?
Share your genetic findings with your primary care provider or a cardiologist for clinical context and confirmation. They can assess your overall cardiovascular health and determine whether baseline evaluations, such as an echocardiogram or nuclear imaging, are warranted.
Sources & further reading
Educational information only, last refreshed 9/8/2026. Not medical advice — these associations describe population statistics, not individual predictions.
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