ClinVar Genomic variation as it relates to human health

The MTHFR c.155G>A (p.Arg52Gln) variant is a missense variant which has been reported in at least five studies in which it is found in at least seven unrelated individuals with homocystinuria due to methylene tetrahydrofolate reductase (MTHFR) deficiency in a homozygous or compound heterozygous state (Goyette et al. 1995; Prasad et al. 2011; Tonetti et al. 2013; D'Aco et al. 2014; Huemer et al. 2016). Four of the affected individuals carried loss of function variants as a second variant. The p.Arg52Gln variant was absent from 300 control alleles and is reported at a frequency of 0.000114 in the European (non-Finnish) population of the Genome Aggregation Database. Expression studies in both patient and non-patient fibroblasts demonstrated reduced MTHFR activity compared to wildtype (Goyette et al. 1995; Huemer et al. 2016; Burda et al. 2017). Based on the collective evidence and application of the ACMG criteria, the p.Arg52Gln variant is classified as pathogenic for methylene tetrahydrofolate reductase deficiency.

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Published functional studies demonstrate reduced enzymatic activity, thermo-stable activity, and NADPH binding affinity in patient cells (Goyette et al., 1995; Burda et al., 2015; Burda et al., 2016); This variant is associated with the following publications: (PMID: 25736335, 7726158, 10923034, 26025547, 33089527, 28537576, 32533987, 21778025, 12406076, 12733064, 27743313, 25079578, 34214447)

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 52 of the MTHFR protein (p.Arg52Gln). This variant is present in population databases (rs754980119, gnomAD 0.01%). This missense change has been observed in individual(s) with methylenetetrahydrofolate reductase deficiency (PMID: 7726158, 10923034, 12733064, 21778025, 25079578, 25736335). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This variant is also known as c.167G>A. ClinVar contains an entry for this variant (Variation ID: 570071). 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 have shown that this missense change affects MTHFR function (PMID: 27743313). For these reasons, this variant has been classified as Pathogenic.

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with homocystinuria due to MTHFR deficiency (MIM#236250). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to glutamine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (14 heterozygotes, 0 homozygotes). (SP) 0501 - Missense variant with conflicting in silico predictions, and highly conserved with a minor amino acid change. (SP) 0600 - Variant is located in the annotated catalytic domain (PMID: 26872964). (I) 0801 - This variant has very strong previous evidence of pathogenicity in unrelated individuals. The variant has previously been observed in at least ten families with homocystinuria due to MTHFR deficiency (MIM#236250) (ClinVar, HGMD, PMID: 7726158, PMID: 26872964). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. The variant results in a modest reduction in enzyme activity compared to wild type, as previously demonstrated by in vitro functional studies (PMID: 27743313). (SP) 1102 - Strong phenotype match for this individual. (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign