ClinVar Miner

Submissions for variant NM_005957.5(MTHFR):c.416C>T (p.Thr139Met)

gnomAD frequency: 0.00001  dbSNP: rs1057519360
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Fulgent Genetics, Fulgent Genetics RCV002503824 SCV002809788 likely pathogenic Homocystinuria due to methylene tetrahydrofolate reductase deficiency; Neural tube defects, folate-sensitive; Schizophrenia; Thrombophilia due to thrombin defect 2021-09-07 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV000416816 SCV003522268 uncertain significance Homocystinuria due to methylene tetrahydrofolate reductase deficiency 2021-08-31 criteria provided, single submitter clinical testing This sequence change replaces threonine with methionine at codon 139 of the MTHFR protein (p.Thr139Met). The threonine residue is moderately conserved and there is a moderate physicochemical difference between threonine and methionine. This variant is not present in population databases (ExAC no frequency). This missense change has been observed in individual(s) with severe MTHFR deficiency (PMID: 15048559). ClinVar contains an entry for this variant (Variation ID: 222893). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). Experimental studies have shown that this missense change affects MTHFR function (PMID: 15048559). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV003235132 SCV003933827 uncertain significance not specified 2023-05-08 criteria provided, single submitter clinical testing Variant summary: MTHFR c.416C>T (p.Thr139Met) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251418 control chromosomes (gnomAD). c.416C>T has been reported in the literature in an individual affected with Homocystinuria Due To Methylene Tetrahydrofolate Reductase Deficiency (example: Yano_2004). At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in 10%-<30% of normal activity (example: Yano_2004). The following publication has been ascertained in the context of this evaluation (PMID: 15048559). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as VUS and likely pathogenic. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
Baylor Genetics RCV003468969 SCV004196394 likely pathogenic Neural tube defects, folate-sensitive 2023-11-27 criteria provided, single submitter clinical testing
University Children's Hospital, University of Zurich RCV000416816 SCV000258402 pathogenic Homocystinuria due to methylene tetrahydrofolate reductase deficiency no assertion criteria provided literature only

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