Submissions for variant NM_005957.5(MTHFR):c.680C>T (p.Thr227Met)

gnomAD frequency: 0.00001  dbSNP: rs748571395

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Centre for Inherited Metabolic Diseases, Karolinska University Hospital	RCV000985005	SCV001554468	pathogenic	Homocystinuria due to methylene tetrahydrofolate reductase deficiency	2021-04-07	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000985005	SCV003492437	pathogenic	Homocystinuria due to methylene tetrahydrofolate reductase deficiency	2024-01-22	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 227 of the MTHFR protein (p.Thr227Met). This variant is present in population databases (rs748571395, gnomAD 0.008%). This missense change has been observed in individual(s) with MTHFR deficiency (PMID: 7726158, 32939339; Invitae; external communication). This variant is also known as C692T. ClinVar contains an entry for this variant (Variation ID: 800827). 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. For these reasons, this variant has been classified as Pathogenic.
Revvity Omics, Revvity	RCV000985005	SCV003808995	uncertain significance	Homocystinuria due to methylene tetrahydrofolate reductase deficiency	2021-08-31	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003461295	SCV004196391	pathogenic	Neural tube defects, folate-sensitive	2023-10-28	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000985005	SCV005077183	pathogenic	Homocystinuria due to methylene tetrahydrofolate reductase deficiency	2024-04-19	criteria provided, single submitter	clinical testing	Variant summary: MTHFR c.680C>T (p.Thr227Met), also reported as "C692T", results in a non-conservative amino acid change in 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 8e-06 in 251488 control chromosomes. c.680C>T has been reported in the literature in multiple homozygous individuals affected with Homocystinuria due to Methylene Tetrahydrofolate Reductase Deficiency (examples: Aljassim_2020, Goyette_1995). These data indicate that the variant is very likely to be associated with disease. At least one publication reports that enzyme activity in patient fibroblasts was <10% of normal activity (Goyette_1995). The following publications have been ascertained in the context of this evaluation (PMID: 32939339, 7726158). ClinVar contains an entry for this variant (Variation ID: 800827). Based on the evidence outlined above, the variant was classified as pathogenic.
Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City	RCV000985005	SCV001132934	pathogenic	Homocystinuria due to methylene tetrahydrofolate reductase deficiency	2019-08-25	no assertion criteria provided	clinical testing