ClinVar

Description

Experimental studies have shown that this missense change affects MTHFR function (PMID: 27743313). 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. ClinVar contains an entry for this variant (Variation ID: 187892). This missense change has been observed in individual(s) with severe methylenetetrahydrofolate reductase deficiency (PMID: 25736335, 31069529). This variant is present in population databases (rs200137991, gnomAD 0.0009%). This sequence change replaces tryptophan, which is neutral and slightly polar, with serine, which is neutral and polar, at codon 421 of the MTHFR protein (p.Trp421Ser). This variant disrupts the p.Trp421 amino acid residue in MTHFR. Other variant(s) that disrupt this residue have been observed in individuals with MTHFR-related conditions (Invitae), which suggests that this may be a clinically significant amino acid residue. 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.