ClinVar Miner

Submissions for variant NM_005957.5(MTHFR):c.1130G>A (p.Arg377His)

gnomAD frequency: 0.00004  dbSNP: rs750323424
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000810485 SCV000950687 pathogenic Homocystinuria due to methylene tetrahydrofolate reductase deficiency 2024-01-25 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 377 of the MTHFR protein (p.Arg377His). This variant is present in population databases (rs750323424, gnomAD 0.004%). This missense change has been observed in individual(s) with methylenetetrahydrofolate reductase deficiency (PMID: 24797679, 25736335, 33089527). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 654511). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on MTHFR protein function. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on MTHFR function (PMID: 27743313). This variant disrupts the p.Arg377 amino acid residue in MTHFR. Other variant(s) that disrupt this residue have been observed in individuals with MTHFR-related conditions (PMID: 8940272, 12673793, 25736335, 26872964), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics RCV003461196 SCV004196398 pathogenic Neural tube defects, folate-sensitive 2024-03-28 criteria provided, single submitter clinical testing
Fulgent Genetics, Fulgent Genetics RCV005012348 SCV005634688 likely pathogenic Homocystinuria due to methylene tetrahydrofolate reductase deficiency; Neural tube defects, folate-sensitive; Schizophrenia; Thrombophilia due to thrombin defect 2024-04-04 criteria provided, single submitter clinical testing
GeneDx RCV005054269 SCV005687924 pathogenic not provided 2024-07-31 criteria provided, single submitter clinical testing Published functional studies demonstrate a damaging effect (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: 25736335, 26025547, 24797679, 34214447, 27743313, 33089527)
Natera, Inc. RCV000810485 SCV002094636 likely pathogenic Homocystinuria due to methylene tetrahydrofolate reductase deficiency 2021-04-26 no assertion criteria provided clinical testing

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