ClinVar Miner

Submissions for variant NM_005957.5(MTHFR):c.971A>G (p.Asn324Ser)

dbSNP: rs267606887
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Molecular Genetics, Royal Melbourne Hospital RCV002225067 SCV002503851 likely pathogenic Homocystinuria due to methylene tetrahydrofolate reductase deficiency 2023-03-30 criteria provided, single submitter clinical testing This sequence change is predicted to replace asparagine with serine at codon 324 of the MTHFR protein, p.(Asn324Ser). The asparagine residue is evolutionary invariant (100 vertebrates, UCSC), and located in the catalytic domain. There is a small physicochemical difference between asparagine and serine. The variant is absent in a large population cohort (gnomAD v2.1), and has been reported in the homozygous state in at least one case with a biochemically established diagnosis of homocystinuria due to methylenetetrahydrofolate reductase deficiency (PMID: 9781030). In vitro enzymatic assays of the variant demonstrated decreased enzyme activity (further reduced when common polymorphism rs1801133 was in cis), and showed responsiveness to flavin adenine dinucleotide (PMID: 12673793). Multiple lines of computational evidence predict a deleterious effect for the missense substitution (7/7 algorithms). Based on the classification scheme RMH ACMG Guidelines v1.2.1, this variant is classified as LIKELY PATHOGENIC. Following criteria are met: PM2, PS3_Supporting, PM3_Supporting, PP3, PP4.
OMIM RCV002225067 SCV000023863 pathogenic Homocystinuria due to methylene tetrahydrofolate reductase deficiency 2003-05-01 no assertion criteria provided literature only

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