ClinVar Miner

Submissions for variant NM_005957.5(MTHFR):c.1263G>C (p.Trp421Cys)

gnomAD frequency: 0.00001  dbSNP: rs200688214
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000702419 SCV000831272 likely pathogenic Homocystinuria due to methylene tetrahydrofolate reductase deficiency 2023-09-27 criteria provided, single submitter clinical testing This sequence change replaces tryptophan, which is neutral and slightly polar, with cysteine, which is neutral and slightly polar, at codon 421 of the MTHFR protein (p.Trp421Cys). This variant is present in population databases (rs200688214, gnomAD 0.007%). This missense change has been observed in individual(s) with clinical features of MTHFR-related conditions (Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 579195). 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. This variant disrupts the p.Trp421 amino acid residue in MTHFR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 25736335, 27743313; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
GeneDx RCV003313135 SCV004012396 likely pathogenic not provided 2023-07-06 criteria provided, single submitter clinical testing Has not been previously published as pathogenic or benign to our knowledge; 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, 27743313)
Natera, Inc. RCV000702419 SCV002094632 uncertain significance Homocystinuria due to methylene tetrahydrofolate reductase deficiency 2019-10-28 no assertion criteria provided clinical testing

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