Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2_SupportingPP5BP4
The NM_005957(MTHFR):c.1970G>C(p.Ter657SerextTer50) variant causes a stop lost change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD Genomes project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting interpretations of pathogenicity (★). Synonymous variant affecting the same amino acid position (i.e. *657*) has been classified as Likely benign.
Verdict is Uncertain_significance. Variant got 1 ACMG points.
GnomAD3 genomesCov.: 33 GnomAD3 exomes AF: 0.0000119AC: 3AN: 251184Hom.: 0 AF XY: 0.0000147AC XY: 2AN XY: 135770 GnomAD4 exome AF: 0.0000164AC: 24AN: 1461786Hom.: 0 AF XY: 0.0000151AC XY: 11AN XY: 727174
Submissions by phenotype
Homocystinuria due to methylene tetrahydrofolate reductase deficiency
|Likely pathogenic, criteria provided, single submitter||clinical testing||Women's Health and Genetics/Laboratory Corporation of America, LabCorp||Apr 26, 2023||Variant summary: MTHFR c.1970G>C (p.X657SerextX50) changes the termination codon and is predicted to lead to an extended protein with additional amino acids added to the normal C-terminus. MTHFR c.1970G>C (p.X657SerextX50) causes a frameshift which results in an extension of the protein. The variant allele was found at a frequency of 1.2e-05 in 251184 control chromosomes. c.1970G>C has been reported in the homozygous state in brothers with severe methylenetetrahydrofolate reductase deficiency (Tonetti_2003) as well as in a an affected patient with unclassified second allele who had <2% residual MTHFR activity in fibroblasts (Huemer_2016). These data indicate that the variant is likely to be associated with disease. While this variant has not been experimentally tested, a different variant resulting in a similar protein extension (p.*657Argextfs*50) has been reported experimentally to lead to <2% MTHFR activity (Burda_2015). The following publications have been ascertained in the context of this evaluation (PMID: 25736335, 26025547, 12733064). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as likely benign, and one laboratory classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely pathogenic. -|
|Uncertain significance, criteria provided, single submitter||clinical testing||Invitae||Feb 09, 2022||This sequence change disrupts the translational stop signal of the MTHFR mRNA. It is expected to extend the length of the MTHFR protein by 50 additional amino acid residues. This variant is present in population databases (rs749490263, gnomAD 0.003%). This protein extension has been observed in individual(s) with severe methylenetetrahydrofolate reductase deficiency (PMID: 12733064). ClinVar contains an entry for this variant (Variation ID: 975602). This variant disrupts the C-terminus of the MTHFR protein. Other variant(s) that disrupt this region (c.1969T>C (p.*657Serext*50)) have been observed in individuals with MTHFR-related conditions (PMID: 25736335). This suggests that this may be a clinically significant region of the protein. 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. -|
|Likely benign, no assertion criteria provided||clinical testing||Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille||Jan 01, 2019||- -|
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