rs28933979 — TTR Val30Met (V30M)

Most common pathogenic TTR variant causing hereditary transthyretin amyloidosis (hATTR) with peripheral neuropathy and cardiomyopathy

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The Val30Met Mutation — hATTR Amyloidosis' Most Common Cause

Transthyretin (TTR) is a protein made primarily in the liver that carries thyroid hormone and vitamin A11 thyroid hormone and vitamin A
TTR binds thyroxine (T4) and retinol-binding protein in plasma, serving as a transporter for these molecules throughout the body through the bloodstream. Normally, TTR exists as a stable four-molecule complex (tetramer). The Val30Met mutation — a single-letter change replacing valine with methionine at position 30 of the mature protein — destabilizes this tetramer, causing it to fall apart and refold into toxic amyloid fibrils that deposit in nerves, the heart, the eyes, and other organs. Without treatment, hereditary transthyretin amyloidosis (hATTR) with Val30Met is a fatal, progressive disease, typically killing within 10–12 years of symptom onset22 10–12 years of symptom onset
Median untreated survival from stage 1 in the Portuguese natural history cohort was 11.6 years.

Val30Met is the most common amyloidogenic TTR mutation worldwide and the sole cause of epidemic-level amyloidosis in three endemic regions33 three endemic regions
Founder effects explain the geographic clustering: separate ancestral mutations spread through isolated communities in northern Portugal, northern Sweden, and Japan: northern Portugal (where it accounts for ~92% of all hATTR cases), northern Sweden, and certain districts of Japan. The mutation is extremely rare in the general population — global carrier frequency is approximately 1 in 10,000 — but in endemic communities it may affect 1–5% of residents.

The Mechanism

The Val30Met substitution (c.148G>A, NM_000371.4) alters TTR's hydrophobic core44 TTR's hydrophobic core
Valine has a smaller, branched side chain; methionine's longer, flexible thioether side chain disrupts the tightly packed core of each TTR monomer, reducing tetramer stability at physiological conditions. The mutant protein dissociates from the tetramer, misfolds into a β-sheet-rich amyloid conformation55 β-sheet-rich amyloid conformation
Amyloid fibrils are long, insoluble protein strands that accumulate as protein plaques in tissues — they resist normal protein clearance mechanisms and progressively destroy the tissue they infiltrate, and deposits into the endoneurium of peripheral nerves (causing polyneuropathy), the myocardium (causing cardiomyopathy), the vitreous of the eye, and less commonly the kidneys, leptomeninges, and gastrointestinal tract.

The inherited TTR gene produces mutant protein lifelong. Because TTR is made almost entirely by the liver, liver transplantation historically halted the supply of new mutant TTR. Modern gene-silencing therapies (patisiran, inotersen) suppress TTR production from the liver non-surgically, and tetramer stabilizers (tafamidis) prevent the existing protein from falling apart.

The Evidence

The evidence base for Val30Met hATTR is among the strongest for any rare genetic disease, with three FDA-approved therapies supported by phase 3 randomized controlled trials.

Tafamidis (tetramer stabilizer): The ATTR-ACT trial66 ATTR-ACT trial
Maurer et al., N Engl J Med, 2018 — 441 patients with transthyretin cardiomyopathy randomized 2:1 to tafamidis or placebo showed tafamidis reduced all-cause mortality by 30% (hazard ratio 0.70, 95% CI 0.51–0.96) and cardiovascular hospitalizations by 32% (relative risk 0.68) vs placebo over 30 months.

Patisiran (RNA interference): The APOLLO trial77 APOLLO trial
Adams et al., N Engl J Med, 2018 — 225 patients with hATTR polyneuropathy demonstrated patisiran significantly reduced disease progression compared to placebo, with patients experiencing improvement in neuropathy impairment scores vs continued worsening in the placebo arm.

Inotersen (antisense oligonucleotide): The NEURO-TTR trial88 NEURO-TTR trial
Benson et al., N Engl J Med, 2018 — 172 patients with hATTR polyneuropathy showed inotersen reduced neuropathy progression (mNIS+7) and improved quality of life vs placebo.

Natural history in the untreated era: A large Portuguese cohort study99 Portuguese cohort study
Coelho et al., Amyloid, 2018 — N=3,160 patients followed through 2016 found median survival from stage 1 was only 11.6 years untreated. Tafamidis reduced mortality by 91% vs untreated in early-onset patients (<50 years). These findings establish that treatment within the first few years dramatically changes the disease course.

Penetrance and age of onset: Val30Met penetrance varies by geography and sex. In Sweden1010 Sweden
Gorram et al., Amyloid, 2021 — 114 Swedish families, 131 parent-offspring pairs, cumulative penetrance was <10% at age 40 but rose to 71% by age 90, with males showing significantly earlier onset. Average genetic anticipation was 11.7 years (disease appears earlier in each generation). In Portuguese families, onset typically occurs in the 30s–40s; in Sweden and France, late onset (>60 years) is more common.

Practical Actions

For TTR Val30Met carriers, the critical message is: early identification plus early treatment dramatically alters outcome. Symptoms typically begin insidiously — numbness and tingling in the feet, unexplained weight loss, carpal tunnel syndrome, or orthostatic hypotension. Carpal tunnel syndrome1111 Carpal tunnel syndrome
Bilateral carpal tunnel syndrome, especially in a young person, has been reported as the first manifestation of hATTR amyloidosis in ~50% of late-onset Val30Met cases appearing years before neuropathy onset is now recognized as an early warning sign.

Genotype-positive carriers who are still asymptomatic should establish care with a specialist (neurologist or cardiologist experienced in amyloidosis) and enter a monitoring program. Once symptoms begin, treatment should start promptly — the existing therapies stabilize but do not reverse established damage. Tafamidis is currently the mainstay of treatment for cardiomyopathy; patisiran or inotersen are used for polyneuropathy. Newer agents (vutrisiran, eplontersen) offer improved dosing convenience.

Interactions

The Val30Met variant's amyloid deposition is modulated by modifier factors not yet captured as single SNPs. The TTR tetramer stabilizer tafamidis works equally across genotypes by stabilizing all TTR tetramers regardless of which subunits carry the Val30Met mutation, making drug-gene interaction simple: carriers benefit, non-carriers do not have TTR amyloid disease to treat.

The Val142Ile variant (rs76992529)1212 Val142Ile variant (rs76992529)
Also called V122I; found in ~3-4% of African Americans and the dominant cause of late-onset cardiac amyloidosis in that population is a distinct TTR mutation causing predominantly cardiac hATTR. No documented gene-gene interaction exists between Val30Met and Val142Ile — these are independent, ancestry-specific mutations in the same gene.

Family testing is especially important. Each child of a Val30Met carrier has a 50% chance of inheriting the mutation. Predictive genetic testing of at-risk adult family members enables surveillance initiation before symptoms, which is when treatment benefit is greatest.

Genotype Interpretations

What each possible genotype means for this variant.

GG No TTR Val30Met Normal

No Val30Met mutation — standard TTR amyloidosis risk

You carry two copies of the normal TTR allele and do not have the Val30Met mutation. You are not at elevated risk for hereditary transthyretin amyloidosis caused by this variant. More than 99.99% of the general population shares this result. Note that age-related wild-type TTR amyloidosis (ATTRwt) can still develop in older adults regardless of genotype, but this is a different condition unrelated to Val30Met.

AG Val30Met Carrier High Risk

Carries one copy of Val30Met — high risk of hereditary amyloidosis

The Val30Met mutation (c.148G>A) destabilizes the TTR tetramer, causing the protein to misfold into amyloid fibrils that accumulate in peripheral nerves and the heart over decades. The single mutant allele is sufficient because even one copy of Val30Met protein can destabilize the tetramer through a dominant-negative mechanism (mixed tetramers containing one or more mutant subunits are also unstable).

Disease course typically follows a predictable progression through clinical stages: Stage 1 (ambulatory without assistance, mild neuropathy), Stage 2 (ambulatory only with assistance), Stage 3 (wheelchair or bed-bound). The rate of progression from stage to stage varies, but without treatment, median survival from stage 1 is approximately 11.6 years in Portuguese cohorts.

Early warning signs include: bilateral carpal tunnel syndrome (especially in younger individuals), unexplained weight loss, orthostatic hypotension, diarrhea/constipation alternating, impotence, and lower-limb numbness and tingling. Vitreous opacities on eye exam are a specific but less common early sign.

Three therapeutic classes now exist: - Tetramer stabilizers (tafamidis, acoramidis): bind and stabilize the intact tetramer, preventing dissociation and amyloid formation. FDA-approved for cardiac hATTR. The ATTR-ACT trial showed 30% mortality reduction. - Gene silencers (patisiran, inotersen, vutrisiran, eplontersen): suppress TTR production in the liver, reducing the pool of mutant and wild-type TTR available to misfold. FDA-approved for polyneuropathy hATTR. - Liver transplantation: historically first-line, now superseded by drug therapies in most centers, though still used in selected cases.

Genetic anticipation (disease appears earlier in each successive generation) has been documented with an average shift of 11.7 years in Swedish families. Males tend to develop earlier onset than females.

AA Homozygous Val30Met Homozygous

Carries two copies of Val30Met — disease risk remains similar to one copy

Homozygosity for Val30Met (two copies of the c.148G>A mutation) is exceedingly rare globally. A Swedish study of nine homozygous individuals found that "homozygosity for the mutation associated with FAP, ATTR Val30Met, does not implicate a more severe phenotype," with survival actually trending slightly longer than heterozygotes. The authors suggested alternative pathways of amyloid formation or unknown modifier genes may explain the unexpectedly mild phenotype in some homozygotes.

All therapeutic options available to heterozygous carriers (tafamidis, patisiran, inotersen, vutrisiran, eplontersen) apply equally to homozygotes — the treatment mechanism (stabilizing TTR tetramers or suppressing liver TTR production) is not genotype-copy-number dependent.