Submissions for variant NM_005957.5(MTHFR):c.155G>A (p.Arg52Gln)

gnomAD frequency: 0.00004  dbSNP: rs754980119

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000690846	SCV000818575	pathogenic	Homocystinuria due to methylene tetrahydrofolate reductase deficiency	2025-01-27	criteria provided, single submitter	clinical testing	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). Invitae Evidence 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 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.
Illumina Laboratory Services, Illumina	RCV000690846	SCV001423742	pathogenic	Homocystinuria due to methylene tetrahydrofolate reductase deficiency	2020-03-17	criteria provided, single submitter	clinical testing	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.
GeneDx	RCV002245591	SCV002513634	likely pathogenic	not provided	2021-11-19	criteria provided, single submitter	clinical testing	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)
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000690846	SCV002557134	pathogenic	Homocystinuria due to methylene tetrahydrofolate reductase deficiency	2022-02-02	criteria provided, single submitter	clinical testing	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
Fulgent Genetics, Fulgent Genetics	RCV002477553	SCV002794708	pathogenic	Homocystinuria due to methylene tetrahydrofolate reductase deficiency; Neural tube defects, folate-sensitive; Schizophrenia; Thrombophilia due to thrombin defect	2024-01-04	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003459684	SCV004196407	pathogenic	Neural tube defects, folate-sensitive	2024-03-30	criteria provided, single submitter	clinical testing