ClinVar Genomic variation as it relates to human health

This variant is interpreted as Likely Pathogenic, for Combined immunodeficiency and megaloblastic anemia with or without hyperhomocysteinemia, autosomal recessive. The following ACMG Tag(s) were applied: PM2 => Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. PP3 => Multiple lines of computational evidence support a deleterious effect on the gene or gene product. PM3 => For recessive disorders, detected in trans with a pathogenic variant (https://www.ncbi.nlm.nih.gov/pubmed/21813566). PP1 => Cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease (https://www.ncbi.nlm.nih.gov/pubmed/21813566). PM1 => Located in a mutational hot spot and/or critical and well-established functional domain (e.g., active site of an enzyme) without benign variation(https://www.uniprot.org/uniprot/P11586).

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 173 of the MTHFD1 protein (p.Arg173Cys). This variant is present in population databases (rs141210410, gnomAD 0.05%). This missense change has been observed in individual(s) with clinical features of methylenetetrahydrofolate dehydrogenase 1 deficiency (PMID: 21813566, 23296427). 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: 446303). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects MTHFD1 function (PMID: 25548164). 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.

Published functional studies suggest a damaging effect with compromised dehydrogenase activity and impaired de novo purine synthesis (Field et al., 2015); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 23296427, 31203817, 31130284, 21813566, 32414565, 25548164)

Variant summary: MTHFD1 c.517C>T (p.Arg173Cys) results in a non-conservative amino acid change located in the Tetrahydrofolate dehydrogenase/cyclohydrolase, NAD(P)-binding domain (IPR020631) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.6e-05 in 251418 control chromosomes. c.517C>T has been reported in the literature as a biallelic compound heterozygous genotype in at-least one individual affected with features of Severe Combined Immunodeficiency (SCID) with megaloblastic anemia, leukopenia, atypical hemolytic uremic syndrome, and neurologic abnormalities in which hydroxocobalamin and folate therapy provided partial immune reconstitution (PMID 25548164). It has also been reported as a homozygous genotype in settings of Primary Immunodeficiency (PID). These data indicate that the variant is likely to be associated with disease (example, PMID: 31203817, 32414565, 25548164, 23296427). At least one publication reports experimental evidence evaluating an impact on protein function, recombinant R173C MTHFD C/D mutant protein exhibited 2.5-fold increased Km for NADP+ (P < 0.01), suggesting that the enzyme produced from this allele has compromised D (dehydrogenase) activity (PMID: 25548164). Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 (P/LP, n=3; VUS, n=1). Based on the evidence outlined above, the variant was classified as likely pathogenic.