chr1-11796321-G-A
Variant summary
Our verdict is Benign. Variant got -9 ACMG points: 3P and 12B. PM1PP3BP4_StrongBA1
The NM_005957.5(MTHFR):c.665C>T(p.Ala222Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.318 in 1,613,846 control chromosomes in the GnomAD database, including 87,723 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as drug response (★★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Synonymous variant affecting the same amino acid position (i.e. A222A) has been classified as Likely benign.
Frequency
Consequence
NM_005957.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -9 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.275 AC: 41856AN: 151970Hom.: 6918 Cov.: 32
GnomAD3 exomes AF: 0.315 AC: 79177AN: 251468Hom.: 14637 AF XY: 0.309 AC XY: 41934AN XY: 135906
GnomAD4 exome AF: 0.323 AC: 471698AN: 1461758Hom.: 80805 Cov.: 40 AF XY: 0.318 AC XY: 231451AN XY: 727162
GnomAD4 genome AF: 0.275 AC: 41850AN: 152088Hom.: 6918 Cov.: 32 AF XY: 0.273 AC XY: 20316AN XY: 74360
ClinVar
Submissions by phenotype
Homocystinuria due to methylene tetrahydrofolate reductase deficiency Pathogenic:2Uncertain:1Benign:2
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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. -
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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. -
not specified Benign:4
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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. -
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not provided Uncertain:1Other:2
- Variant classified as "other reportable" ??? variant is clinically benign (not associated with disease) but is reported when observed (e.g. pseudodeficiency alleles).
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. -
MTHFR: PM3, PM2:Supporting -
MTHFR THERMOLABILE POLYMORPHISM Pathogenic:1Benign:1
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Neural tube defects, folate-sensitive Benign:2
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See cases Uncertain:1
ACMG categories: PS3,PS4,PM1,BA1 -
Gastrointestinal stromal tumor Uncertain:1
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Thrombophilia due to thrombin defect Uncertain:1
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methotrexate response - Toxicity Other:1
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. Drug-variant association: Toxicity
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at