ClinVar Genomic variation as it relates to human health

The c.1129C>T; p.Arg377Cys variant has been reported multiple times in the literature. An African-American/Caucasian female with lethargy and failure to thrive at one month of age, and seizures, apnea, and hypotonia at three months of age was reported to be compound heterozygous for this variant as well as p.Leu323Pro (Goyette 1996). A 13-year-old male with developmental delay was reported to be compound heterozygous for the p.Arg377Cys and p.Met338Thr variants (Sibani 2003), and a study of families diagnosed with severe MTHFR deficiency reported two further individuals heterozygous for p.Arg377Cys and either p.His181Asp or p.Cys193Tyr (Tonetti 2003). A study of an Amish community found four children homozygous for the p.Arg377Cys variant, all of whom had slow head growth and arrested development in the first few months of life; while 68 heterozygotes were among 230 healthy individuals in the community, for an estimated population carrier frequency of 30% (Strauss 2007). The four p.Arg377Cys homozygotes all displayed elevated plasma N-homocysteinylated protein, Hcy-thiolactone and total homocysteine concentrations (Jakubowski 2008). This variant is listed in the genome Aggregation Database (gnomAD) with an overall population frequency of 0.004% (identified on 5 out of 126,714 chromosomes) and an East Asian population frequency of zero (out of 18,870 chromosomes), while the Exome Sequencing Project reports the variant frequency as 0.008% (identified on 1 out of 13,005 chromosomes). However, a study of congenital heart disease risk in China identified the p.Arg377Cys variant in a homozygous state in 12 healthy individuals and 27 affected patients among 467 studied Chinese Han individuals, with an allele frequency of over 25% (Zhang 2014). The discrepancy between this report and those of the population databases has not yet been explained. Although these findings are suggestive, based on the available evidence, the clinical significance of the p.Arg377Cys variant cannot be determined with certainty.

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 377 of the MTHFR protein (p.Arg377Cys). This variant is present in population databases (rs121434296, gnomAD 0.004%). This missense change has been observed in individual(s) with clinical features of severe MTHFR deficiency and/or MTHFR deficiency (PMID: 8940272, 12673793, 17409006, 25736335, 26025547, 26872964; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It is commonly reported in individuals of Amish ancestry (PMID: 17409006). This variant is also known as C1141T. ClinVar contains an entry for this variant (Variation ID: 3528). 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. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on MTHFR function (PMID: 10551815, 27743313, 34214447). This variant disrupts the p.Arg377 amino acid residue in MTHFR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10923034, 26025547). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.

Variant summary: MTHFR c.1129C>T (p.Arg377Cys) results in a non-conservative amino acid change located in the MTHFR, SAM-binding regulatory domain (IPR053806) 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 2e-05 in 251484 control chromosomes (gnomAD). c.1129C>T has been reported in the literature in multiple individuals including homozygotes affected with Homocystinuria Due To Methylene Tetrahydrofolate Reductase Deficiency (examples : Strauss_2007, Gowda_2021, Ghosh_2017). These data indicate that the variant is very likely to be associated with disease. In vitro functional assays show reduced activity for the variant (Burda_2017). The following publications have been ascertained in the context of this evaluation (PMID: 17409006, 34347262, 28468868, 27743313). ClinVar contains an entry for this variant (Variation ID: 3528). Based on the evidence outlined above, the variant was classified as pathogenic.