ClinVar Miner

Submissions for variant NM_005957.4(MTHFR):c.1263G>C (p.Trp421Cys)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000702419 SCV000831272 uncertain significance Homocysteinemia due to MTHFR deficiency 2018-07-10 criteria provided, single submitter clinical testing This sequence change replaces tryptophan with cysteine at codon 421 of the MTHFR protein (p.Trp421Cys). The tryptophan residue is highly conserved and there is a large physicochemical difference between tryptophan and cysteine. This variant is present in population databases (rs200688214, ExAC 0.01%). This variant has not been reported in the literature in individuals with MTHFR-related disease. 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: "Probably Damaging"; Align-GVGD: "Class C0"). The observation of one or more missense substitutions at this codon (p.Trp421Cys, p.Trp421Ser) in affected individuals suggests that this may be a clinically significant residue (PMID: 25736335, 27743313, Invitae). 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.

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