Submissions for variant NM_005957.5(MTHFR):c.459C>G (p.Ile153Met)

gnomAD frequency: 0.00005  dbSNP: rs767890671

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India	RCV001290317	SCV001478368	pathogenic	Homocystinuria due to methylene tetrahydrofolate reductase deficiency		criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002499515	SCV002810470	likely pathogenic	Homocystinuria due to methylene tetrahydrofolate reductase deficiency; Neural tube defects, folate-sensitive; Schizophrenia; Thrombophilia due to thrombin defect	2024-03-28	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001290317	SCV003522743	likely pathogenic	Homocystinuria due to methylene tetrahydrofolate reductase deficiency	2025-01-15	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 153 of the MTHFR protein (p.Ile153Met). This variant is present in population databases (rs767890671, gnomAD 0.09%). This missense change has been observed in individual(s) with clinical features of methylene tetrahydrofolate reductase deficiency. (PMID: 12673793, 25736335, 33089527, 35322348, 35499206). ClinVar contains an entry for this variant (Variation ID: 996033). 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: 34214447). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Revvity Omics, Revvity	RCV001290317	SCV003828366	likely pathogenic	Homocystinuria due to methylene tetrahydrofolate reductase deficiency	2023-08-10	criteria provided, single submitter	clinical testing
Neuberg Centre For Genomic Medicine, NCGM	RCV001290317	SCV004101536	likely pathogenic	Homocystinuria due to methylene tetrahydrofolate reductase deficiency	2023-05-20	criteria provided, single submitter	clinical testing	The observed missense c.459C>G(p.Ile153Met) variant in MTHFR gene has been reported in compound heterozygous state in patient(s) affected with Homocystinuria (Sibani S, et. al.,2003; Marelli C, et. al.,2021). Experimental studies have shown that this missense change affects MTHFR function (Weile J, et. al., 2021). This variant is present with an allele frequency of 0.01% in gnomAD Exomes database. This variant has been reported to the ClinVar database as Pathogenic/ Likely Pathogenic (multiple submissions). Multiple lines of computational evidence (Polyphen - probably damaging , SIFT - damaging and MutationTaster - disease causing) predict a damaging effect on protein structure and function for this variant. The amino acid change p.Ile153Met in MTHFR is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Ile at position 153 is changed to a Met changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Likely Pathogenic. In absence of another reportable variant in MTHFR gene, the molecular diagnosis is not confirmed.
Baylor Genetics	RCV003462851	SCV004196386	likely pathogenic	Neural tube defects, folate-sensitive	2024-03-29	criteria provided, single submitter	clinical testing
Genetics and Genomic Medicine Centre, NeuroGen Healthcare, NeuroGen Healthcare	RCV001290317	SCV005873778	pathogenic	Homocystinuria due to methylene tetrahydrofolate reductase deficiency	2021-09-28	criteria provided, single submitter	clinical testing
GeneDx	RCV005367813	SCV005921357	pathogenic	not provided	2024-10-15	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 26872964, 25736335, 30212743, 33089527, 34214447, 35322348, 35499206, 12673793)