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Methylenetetrahydrofolate Reductase mutations

Item Value
Approval req'd? No
Available Stat? No
Utilization Guidelines Tests with long turn-around times (ie. Molecular based tests and Microarrays) should only be requested on an inpatient if the result is going to affect the inpatient management.

If the patient will likely be discharged before the result will be available, the test should be requested after discharge. (NOTE: UCSF Medical Center is not reimbursed for inpatient testing).

An exception to the above may be appropriate if there is a possibility the patient will not survive to be discharged and the information is important for diagnosis and/or family decisions/management (ie. recurrence risk).
Test code MTR
Test group Thrombosis risk
Performed by Medical Genomics - Molecular Diagnostics
In House Availability Run once per week, or as needed, day shift only
Method PCR and allele-specific probes
Collection Instructions Do not collect sample in heparin. Keep sample refrigerated for overnight or longer storage.
Container type Lavender top preferred, Blue top and Yellow (ACD) tops acceptable
Amount to Collect 3 mL blood (Note this volume is sufficient to perform all thrombosis risk factor mutations)
Sample type Whole blood
Preferred volume 3 mL blood (Note this volume is sufficient to perform all thrombosis risk factor mutations)
Min. Volume 1.5 mL blood
UCSF Rejection Criteria Heparinized (green top) samples.
Processing notes Do not centrifuge the specimen. Store at room temperature. Refrigerated samples are acceptable.
Normal range Negative
Synonyms Thrombosis risk mutations; MTHFR mutations; Hyperhomocysteinemia; Hypercoagulability; Methylene Tetrahydrofolate Reductase mutations
Turn around times 7-10 days
Additional information Mutations
NM_005957.4(MTHFR):c.665C>T (p.Ala222Val), also known as 677C>T variant
NM_005957.4(MTHFR):c.1286A>C (p.Glu429Ala), also known as 1298A>C variant

Incidence
The allele frequencies of the c.665C>T and c.1286A>C variants are 31-35% in European Caucasians and 12-15% in African Americans. Homozygosity for the 677C>T mutation occurs in 10–20% of the general population. These two variants are in linkage disequilibrium with each another, and therefore a combination of both variants is usually seen only in individuals who are compound heterozygotes in trans.

Pathogenicity
The two mutations detected by this assay result in a thermolabile protein and reduce enzyme activity by decreasing the availability of the N-methyltetrahydrofolate, which is required in the remethylation reaction that regulates plasma homocysteine levels. As a result, homocysteine levels may be elevated.

Thrombosis Risk (2013 ACMG practice guidelines*)
Recent meta-analyses have disproven an association between the MTHFR 677C>T and 1298A>C variants and an increased risk for VTE as well as hyperhomocysteinemia and risk for coronary heart disease. However, homozygosity for the MTHFR 665C>T variant predisposes to mild hyperhomocysteinemia, usually in the setting of suboptimal folate levels. A fasting plasma homocysteine level could be obtained in case of homozygosity for the MTHFR 665C>T variant, in order to provide more information for counseling.

Homozygosity for the MTHFR 665C>T variant AND elevated plasma homocysteine levels may represent a mildly increased risk for thromboembolism (odds ratio 1.27) and recurrent pregnancy loss (odds ratio 2.7).

The heterozygous variant 665C>T, the homozygous variant c.1286A>C, and the compound heterozygous 665C>T with c.1286A>C are all unlikely to represent independent risk factors for venous thromboembolism or hyperhomocysteinemia.


*Hickey et al. Gen. Med. 15:153-156, 2013.
Bezemer ID et al. Arch Intern Med 167:497–501, 2007

If a mutation was detected, genetic counseling is recommended for this patient.

An interpretation of this test by a laboratory physician will automatically be performed and billed for separately.

This test was developed and its performance characteristics determined by the Clinical Laboratories at the Medical Center at UC San Francisco. It has not been cleared or approved by the U.S. Food and Drug Administration.
CPT coding 81291
LOINC code 38415-6
LDT or Mod FDA? Yes
Last Updated 7/19/2017 9:07:21 PM
Entry Number 1285
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