ClinVar Miner

Submissions for variant NM_005957.4(MTHFR):c.665C>T (p.Ala222Val) (rs1801133)

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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000153516 SCV000884146 uncertain significance not provided 2017-05-02 criteria provided, single submitter clinical testing One copy of the c.665C>T; p.Ala222Val variant, also known as C677T or thermolabile variant, was detected in the MTHFR gene by massively parallel sequencing and confirmed by Sanger sequencing. This variant is observed in the general population at an overall allele frequency of 30.8% (85329/277132 alleles, including 15447 homozygotes) in the Genome Aggregation Database. This variant has been studied extensively and is considered a ''susceptibility'' or an ''association'' variant. The thermolabile c.665C>T in a homozygous state has been correlated with reduced enzyme activity and increased homocysteine (Frosst 1995). Recent publication of the American College of Medical Genetics stated that this variant, c.665C>T; p.Ala222Val, in the heterozygous form is unlikely to be of clinical significance (Hickey 2013); however, a possible effect of this variant when paired with the pathogenic MTHFR variant, on the opposite chromosome cannot be excluded. Deep intronic variants and variants in the untranslated region are not analyzed by this method; therefore, another pathogenic MTHFR variant cannot be ruled out.
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 Venous thrombosis 2017-12-30 no assertion criteria provided curation
Department of Pharmacy and Biotechnology,University of Bologna RCV000144921 SCV000187678 uncertain significance Gastrointestinal stroma tumor no assertion criteria provided case-control
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000153516 SCV000203040 other not provided 2017-01-13 criteria provided, single submitter clinical testing
FirmaLab RCV000003697 SCV000106043 pathogenic MTHFR deficiency, thermolabile type no assertion criteria provided 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.
Illumina Clinical Services Laboratory,Illumina RCV000259890 SCV000347807 likely benign Neural tube defects, folate-sensitive 2016-06-14 criteria provided, single submitter clinical testing
OMIM RCV000003697 SCV000023860 benign MTHFR deficiency, thermolabile type 2019-06-11 no assertion criteria provided literature only
PharmGKB RCV000211133 SCV000268236 drug response cyclophosphamide response - Toxicity/ADR 2016-07-11 reviewed by expert panel curation PharmGKB Level of Evidence 2A: Annotation for a variant-drug combination that qualifies for level 2B where the variant is within a VIP (Very Important Pharmacogene) as defined by PharmGKB. The variants in level 2A are in known pharmacogenes, so functional significance is more likely.
PharmGKB RCV000211336 SCV000268238 drug response carboplatin response - Efficacy 2016-07-11 reviewed by expert panel curation PharmGKB Level of Evidence 2A: Annotation for a variant-drug combination that qualifies for level 2B where the variant is within a VIP (Very Important Pharmacogene) as defined by PharmGKB. The variants in level 2A are in known pharmacogenes, so functional significance is more likely.
PharmGKB RCV000417131 SCV000494694 drug response methotrexate response - Dosage, Efficacy, Toxicity/ADR 2018-05-14 reviewed by expert panel curation PharmGKB Level of Evidence 2A: Annotation for a variant-drug combination that qualifies for level 2B where the variant is within a VIP (Very Important Pharmacogene) as defined by PharmGKB. The variants in level 2A are in known pharmacogenes, so functional significance is more likely.

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