ClinVar Miner

Submissions for variant NM_005957.5(MTHFR):c.470G>A (p.Arg157Gln)

gnomAD frequency: 0.00002  dbSNP: rs121434295
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV001382824 SCV001581759 pathogenic Homocystinuria due to methylene tetrahydrofolate reductase deficiency 2024-10-30 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 157 of the MTHFR protein (p.Arg157Gln). This variant is present in population databases (rs121434295, gnomAD 0.01%). This missense change has been observed in individual(s) with MTHFR deficiency (PMID: 7920641, 10679944, 25736335). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This variant is also known as 482G>A. ClinVar contains an entry for this variant (Variation ID: 3519). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt MTHFR protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects MTHFR function (PMID: 27743313). For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics, Fulgent Genetics RCV002476918 SCV002801356 likely pathogenic Homocystinuria due to methylene tetrahydrofolate reductase deficiency; Neural tube defects, folate-sensitive; Schizophrenia; Thrombophilia due to thrombin defect 2021-12-28 criteria provided, single submitter clinical testing
Baylor Genetics RCV003460410 SCV004196396 likely pathogenic Neural tube defects, folate-sensitive 2023-12-09 criteria provided, single submitter clinical testing
GeneDx RCV004719616 SCV005325184 pathogenic not provided 2024-01-09 criteria provided, single submitter clinical testing Published functional studies found this variant is associated with significantly reduced MTHFR activity and reduced thermal stability compared to wild-type (PMID: 27743313); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 31589614, 33574475, 29524840, 35008593, 36358396, 34214447, 7920641, 25736335, 33089527, 26872964, 31645654, 10679944, 27743313)
OMIM RCV001382824 SCV000023859 pathogenic Homocystinuria due to methylene tetrahydrofolate reductase deficiency 1994-06-01 no assertion criteria provided literature only
Natera, Inc. RCV001382824 SCV002094648 pathogenic Homocystinuria due to methylene tetrahydrofolate reductase deficiency 2020-01-20 no assertion criteria provided clinical testing

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