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

gnomAD frequency: 0.27446  dbSNP: rs1801133

Total submissions: 21

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
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	2023-11-29	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. 1995 May;10(1):111-3. PMID: 7647779. Hickey SE et al. ACMG Practice Guideline: lack of evidence for MTHFR polymorphism testing. Genet Med. 2013 Feb;15(2):153-6. PMID: 23288205.
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	2024-01-01	criteria provided, single submitter	clinical testing	MTHFR: PM3, PM2:Supporting
Myriad Genetics, 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001030751	SCV001733273	benign	Homocystinuria due to methylene tetrahydrofolate reductase deficiency	2024-02-01	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University Hospital Muenster	RCV004584309	SCV002506425	uncertain significance	See cases	2022-01-06	criteria provided, single submitter	clinical testing	ACMG categories: PS3,PS4,PM1,BA1
OMIM	RCV000003697	SCV000023860	benign	MTHFR THERMOLABILE POLYMORPHISM	2023-09-29	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, Sultan Qaboos University	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.	RCV001030751	SCV001463167	benign	Homocystinuria due to methylene tetrahydrofolate reductase 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