ClinVar Miner

Submissions for variant NM_005957.5(MTHFR):c.665C>T (p.Ala222Val)

gnomAD frequency: 0.27446  dbSNP: rs1801133
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Total submissions: 22
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
PharmGKB RCV001787367 SCV002031238 drug response methotrexate response - Metabolism/PK 2021-10-21 reviewed by expert panel curation PharmGKB Level of Evidence 2A: Variants in Level 2A clinical annotations are found in PharmGKB’s Tier 1 Very Important Pharmacogenes (VIPs). These variants are in known pharmacogenes, implying causation of drug phenotype is more likely. These clinical annotations describe variant-drug combinations with a moderate level of evidence supporting the association. For example, the association may be found in multiple cohorts, but there may be a minority of studies that do not support the majority assertion. Level 2A clinical annotations must be supported by at least two independent publications.
PharmGKB RCV001847567 SCV002031239 drug response methotrexate response - Toxicity 2021-03-24 reviewed by expert panel curation PharmGKB Level of Evidence 2A: Variants in Level 2A clinical annotations are found in PharmGKB’s Tier 1 Very Important Pharmacogenes (VIPs). These variants are in known pharmacogenes, implying causation of drug phenotype is more likely. These clinical annotations describe variant-drug combinations with a moderate level of evidence supporting the association. For example, the association may be found in multiple cohorts, but there may be a minority of studies that do not support the majority assertion. Level 2A clinical annotations must be supported by at least two independent publications.
Eurofins NTD LLC (GA) RCV000153516 SCV000203040 other not provided 2017-01-13 criteria provided, single submitter clinical testing
GeneDx RCV000428048 SCV000519504 benign not specified 2016-04-25 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000153516 SCV000884146 uncertain significance not provided 2022-01-06 criteria provided, single submitter clinical testing The MTHFR c.665C>T; p.Ala222Val variant (rs1801133), also known as C677T or the thermolabile variant, is listed in the ClinVar database (Variation ID: 3520) and is observed in the general population with an overall allele frequency of 30.8% (87,234/282,784 alleles including 15,819 homozygotes) in the Genome Aggregation Database. The thermolabile c.665C>T variant in the homozygous state has been correlated with reduced enzyme activity and increased homocysteine (Frosst 1995). The practice guidelines from The American College of Medical Genetics state that this variant in the heterozygous state is unlikely to be of clinical significance (Hickey 2013); however, a possible effect of this variant when paired with a pathogenic MTHFR variant on the opposite chromosome cannot be excluded. Additionally, the practice guidelines state that an individual who is homozygous for the c.665C>T; p.Ala222Val variant and has elevated homocysteine may be at mildly increased risk for venous thromboembolism and recurrent pregnancy loss (Hickey 2013). The variant is considered a ''susceptibility'' or an ''association'' variant. References: Frosst P et al. A candidate genetic risk factor for vascular disease: A common mutation in methylenetetrahydrofolate reductase. Nat. Genet. 10, 111–113. Hickey SE et al. ACMG Practice Guideline: lack of evidence for MTHFR polymorphism testing. Genet Med 2013; 15(2):153-156.
Mendelics RCV000259890 SCV001135171 likely benign Neural tube defects, folate-sensitive 2019-05-28 criteria provided, single submitter clinical testing
CeGaT Center for Human Genetics Tuebingen RCV000153516 SCV001147149 uncertain significance not provided 2016-10-01 criteria provided, single submitter clinical testing
Myriad Women's Health, Inc. RCV001030751 SCV001194043 pathogenic Homocystinuria due to methylene tetrahydrofolate reductase deficiency 2019-12-16 criteria provided, single submitter clinical testing NM_005957.4(MTHFR):c.665C>T(A222V) is a common variant present in approximately 30% of the general population. While many individuals who are homozygous for this variant are asymptomatic, some may have mild MTHFR deficiency associated with increased plasma homocysteine. Sources cited for classification include the following: PMID 7647779, 8837319, 9545406, 11781870, 12560871, 8903338, 9789068, 11929966, 15565101, 17436239, 12356947, 9133512, 12196644 and 9798595. Classification of NM_005957.4(MTHFR):c.665C>T(A222V) is based on the following criteria: This is a well-established variant in the literature that has been observed more frequently in patients with mild MTHFR deficiency than in healthy populations and there is functional data showing deficient protein function. Please note: this variant was assessed in the context of healthy population screening.
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV001030751 SCV001366606 pathogenic Homocystinuria due to methylene tetrahydrofolate reductase deficiency 2019-01-17 criteria provided, single submitter clinical testing This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: No criteria apply. This variant was detected in homozygous state.
Invitae RCV001030751 SCV001733273 benign Homocystinuria due to methylene tetrahydrofolate reductase deficiency 2021-12-18 criteria provided, single submitter clinical testing
Institute of Human Genetics, University Hospital Muenster RCV002227012 SCV002506425 uncertain significance Stroke 2022-01-06 criteria provided, single submitter clinical testing ACMG categories: PS3,PS4,PM1,BA1
OMIM RCV000003697 SCV000023860 benign MTHFR THERMOLABILE POLYMORPHISM 2019-06-11 no assertion criteria provided literature only
FirmaLab,FirmaLab RCV000003697 SCV000106043 pathogenic MTHFR THERMOLABILE POLYMORPHISM no assertion criteria provided clinical testing
Department of Pharmacy and Biotechnology,University of Bologna RCV000144921 SCV000187678 uncertain significance Gastrointestinal stromal tumor no assertion criteria provided case-control
Database of Curated Mutations (DoCM) RCV000427078 SCV000505736 not provided Neoplasm of stomach 2016-03-10 no assertion provided literature only
Department of Genetics,Sultan Qaboos University Hospital, Oman RCV000761447 SCV000891532 uncertain significance Thrombophilia due to thrombin defect 2017-12-30 no assertion criteria provided curation
Neurology Department,Peking University First Hospital RCV001030751 SCV001423141 uncertain significance Homocystinuria due to methylene tetrahydrofolate reductase deficiency 2020-04-23 no assertion criteria provided research
Natera, Inc. RCV001276670 SCV001463167 benign Homocystinuria due to MTHFR deficiency 2019-12-07 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000428048 SCV001549379 benign not specified no assertion criteria provided clinical testing
Clinical Genetics, Academic Medical Center RCV000428048 SCV001917884 benign not specified no assertion criteria provided clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht RCV000428048 SCV001930296 benign not specified no assertion criteria provided clinical testing
iDNA Genomics RCV000259890 SCV002538647 likely benign Neural tube defects, folate-sensitive no assertion criteria provided reference population

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