ClinVar Miner

Submissions for variant NM_005957.4(MTHFR):c.1130G>A (p.Arg377His)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000810485 SCV000950687 likely pathogenic Homocysteinemia due to MTHFR deficiency 2018-09-25 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 377 of the MTHFR protein (p.Arg377His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs750323424, ExAC 0.01%). This variant has been observed to segregate with methylenetetrahydrofolate reductase deficiency in a family (PMID: 24797679), and has been observed in several additional affected individuals (PMID: 25736335). Experimental studies have shown that this missense change affects enzyme activity in vitro (PMID: 27743313). This variant disrupts the p.Arg377 amino acid residue in MTHFR. Another variant that disrupts this residue has been observed in affected individuals (PMID: 26872964, 12673793, 8940272, 25736335), 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.

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