Test Catalog

Test ID: ATTRZ    
TTR Gene, Full Gene Analysis, Varies

Useful For Suggests clinical disorders or settings where the test may be helpful

Diagnosis of adult individuals suspected of having transthyretin-associated familial amyloidosis

Testing Algorithm Delineates situations when tests are added to the initial order. This includes reflex and additional tests.

See Amyloidosis (Familial) Test Algorithm in Special Instructions.

Clinical Information Discusses physiology, pathophysiology, and general clinical aspects, as they relate to a laboratory test

The systemic amyloidoses are a number of disorders of varying etiology characterized by extracellular protein deposition. The most common form is an acquired amyloidosis secondary to multiple myeloma or monoclonal gammopathy of unknown significance (MGUS) in which the amyloid is composed of immunoglobulin light chains. In addition to light chain amyloidosis, there are a number of acquired amyloidoses caused by the misfolding and precipitation of a wide variety of proteins. There are also hereditary forms of amyloidosis. Due to the clinical overlap between the acquired and hereditary forms, it is imperative to determine the specific type of amyloidosis in order to provide an accurate prognosis and consider appropriate therapeutic interventions.


The most common hereditary amyloidosis is familial transthyretin amyloidosis; an autosomal dominant disorder caused by mutations in the transthyretin (TTR) gene. The resulting amino acid substitutions lead to a relatively unstable, amyloidogenic TTR protein. Most individuals begin to exhibit clinical symptoms between the third and seventh decades of life. Typically, TTR-associated amyloidosis is progressive over a course of 5 to 15 years and the most common cause of death is cardiomyopathy. Affected individuals may present with a variety of symptoms, including peripheral neuropathy, blindness, cardiomyopathy, nephropathy, autonomic nervous dysfunction, or bowel dysfunction.


More than 90 mutations have now been identified within the TTR gene, which cause TTR-associated familial amyloidosis. Most of the mutations described to date are single base pair changes that result in an amino acid substitution. Some of these mutations correlate with the clinical presentation of amyloidosis. However, several different mutations have been identified which exhibit considerable clinical overlap.


It is important to note that this assay does not detect mutations associated with non-TTR forms of familial amyloidosis. Therefore, it is important to first test an affected family member to determine if TTR is involved and to document a specific mutation in the family before testing at risk individuals.

Reference Values Describes reference intervals and additional information for interpretation of test results. May include intervals based on age and sex when appropriate. Intervals are Mayo-derived, unless otherwise designated. If an interpretive report is provided, the reference value field will state this.

An interpretive report will be provided.

Interpretation Provides information to assist in interpretation of the test results

All detected alterations are evaluated according to American College of Medical Genetics recommendations.(1) Variants are classified based on known, predicted, or possible pathogenicity and reported with interpretive comments detailing their potential or known significance.

Cautions Discusses conditions that may cause diagnostic confusion, including improper specimen collection and handling, inappropriate test selection, and interfering substances

A small percentage of individuals who are carriers or have a diagnosis of transthyretin (TTR)-associated amyloidosis may have a mutation that is not identified by this method (eg, large genomic deletions/ duplications, promoter mutations, deep intronic mutations). The absence of a mutation, therefore, does not eliminate the possibility of positive carrier status or the diagnosis of TTR-associated amyloidosis. For carrier testing, it is important to first document the presence of a TTR gene mutation in an affected family member.


Test results should be interpreted in the context of clinical findings, family history, and other laboratory data. Errors in our interpretation of results may occur if information given is inaccurate or incomplete.


Mutations in other genes, such as lysozyme, apolipoprotein AII, gelsolin, and others, have been shown to cause other forms of familial amyloidosis. Abnormalities in these genes are not detected by this assay.


Technical Limitations:

In some cases, DNA variants of undetermined significance may be identified.


Rare polymorphisms exist that could lead to false-negative or false-positive results. If results obtained do not match the clinical findings, additional testing should be considered.


A previous bone marrow transplant from an allogenic donor will interfere with testing. Call 800-533-1710 for instructions for testing patients who have received a bone marrow transplant.  


Evaluation Tools:

Multiple in-silico evaluation tools were used to assist in the interpretation of these results. These tools are updated regularly; therefore, changes to these algorithms may result in different predictions for a given alteration. Additionally, the predictability of these tools for the determination of pathogenicity is currently unvalidated.


Unless reported or predicted to cause disease, alterations in protein coding genes that do not result in an amino acid substitution are not reported.  These and common polymorphisms identified for this patient are available upon request.


Reclassification of Variants-Policy:

All detected alterations are evaluated according to American College of Medical Genetics and Genomics recommendations. Variants are classified based on known, predicted, or possible pathogenicity and reported with interpretive comments detailing their potential or known significance. At this time, it is not standard practice for the laboratory to systematically review likely pathogenic alterations or variants of uncertain significance that have been previously detected and reported. The laboratory encourages health care providers to contact the laboratory at any time to learn how the status of a particular variant may have changed over time.

Supportive Data

DNA sequence analysis was performed on 196 specimens (17 patients with a known transthyretin mutation, 48 patients tested by mass spectrometry, 91 patients with amyloidosis, and 40 normal individuals).

Clinical Reference Recommendations for in-depth reading of a clinical nature

1. Richards S, Aziz N, Bale S, et al: Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med 2015 May;17(5):405-424

2. Benson MD: The hereditary amyloidoses. Best Pract Res Clin Rhematol 2003;17:909-927

3. Eneqvist T, Sauer-Eriksson AE: Structural distribution of mutations associated with familial amyloidotic polyneuropathy in human transthyretin. Amyloid 2001;8:149-168

4. Connors LH, Lim A, Prokaeva VA, et al: Tabulation of human transthyretin (TTR) variants, 2003. Amyloid 2003;10:160-184

Special Instructions Library of PDFs including pertinent information and forms related to the test