Submissions for variant NM_005957.5(MTHFR):c.973C>T (p.Arg325Cys)

gnomAD frequency: 0.00001  dbSNP: rs371085894

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Centogene AG - the Rare Disease Company	RCV001786456	SCV002028302	uncertain significance	Homocystinuria due to methylene tetrahydrofolate reductase deficiency	2021-08-31	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001786456	SCV002292527	uncertain significance	Homocystinuria due to methylene tetrahydrofolate reductase deficiency	2022-07-25	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 325 of the MTHFR protein (p.Arg325Cys). This variant is present in population databases (rs371085894, gnomAD 0.006%). This missense change has been observed in individual(s) with MTHFR deficiency (PMID: 7726158). This variant is also known as C985T, Arg->Cys. ClinVar contains an entry for this variant (Variation ID: 975600). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C25"). 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.
Baylor Genetics	RCV003469485	SCV004196417	pathogenic	Neural tube defects, folate-sensitive	2024-03-07	criteria provided, single submitter	clinical testing
Neuberg Centre For Genomic Medicine, NCGM	RCV001786456	SCV005400735	uncertain significance	Homocystinuria due to methylene tetrahydrofolate reductase deficiency	2023-06-22	criteria provided, single submitter	clinical testing	The observed missense c.973C>T(p.Arg325Cys) variant in MTHFR gene has been reported previously in homozygous state in individual(s) affected with homocystinuria, a wide range of neurological and vascular disturbances and demyelinating disease (Biesalski et al., 2022). This variant is reported with the allele frequency of 0.002% in the gnomAD Exomes. This variant has been reported to the ClinVar database with varying interpretation: Uncertain Significance / Likely Benign. The amino acid Arg at position 325 is changed to a Cys changing protein sequence and it might alter its composition and physico-chemical properties. The amino acid change p.Arg325Cys in MTHFR is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. Multiple lines of computational evidence (Polyphen - Possibly Damaging, SIFT - Damaging, and MutationTaster - Disease causing) predict a damaging effect on protein structure and function for this variant. For these reasons, this variant has been classified as Uncertain Significance.
Fulgent Genetics, Fulgent Genetics	RCV005012694	SCV005634795	likely 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
Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille	RCV001252318	SCV001428070	likely benign	Intellectual disability	2019-01-01	no assertion criteria provided	clinical testing
Solve-RD Consortium	RCV004769976	SCV005091329	likely pathogenic	Thrombophilia due to thrombin defect	2022-06-01	no assertion criteria provided	provider interpretation	Variant confirmed as disease-causing by referring clinical team