Submissions for variant NM_005957.5(MTHFR):c.1286A>C (p.Glu429Ala)

gnomAD frequency: 0.25830  dbSNP: rs1801131

Total submissions: 21

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000153515	SCV000203039	other	not provided	2017-01-13	criteria provided, single submitter	clinical testing
GeneDx	RCV000153515	SCV000519507	benign	not provided	2021-02-25	criteria provided, single submitter	clinical testing	E429A, commonly reported as c.1298A>C, is a benign variant. It results in reduced MTHFR activity but it is not associated with increased plasma folate concentration in the heterozygous or homozygous state. This variant is present in 31% of alleles in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 9545395, 18842806, 21241403, 22882325, 18836720, 21577095, 20135343, 23652803, 18992148, 23162020, 23771968, 19936946, 19837268, 20031554, 19232336, 19356065, 11875032, 22102315, 21897766, 21334398, 21845428, 20935396, 20532637, 21080081, 18583979, 21613384, 19854238, 21107737, 11395038, 9719624, 26238013, 27068821, 27330833, 23659764, 24109560, 23685927, 11274424, 29600437, 24440586, 22051736, 29395581, 20078877, 24175756, 24488901, 24301776, 22576927, 25573130, 29974397, 26135458, 23523621, 16489479)
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000153515	SCV000604289	benign	not provided	2023-11-29	criteria provided, single submitter	clinical testing
Mendelics	RCV000350590	SCV001135170	benign	Neural tube defects, folate-sensitive	2019-05-28	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000153515	SCV001147148	benign	not provided	2023-07-01	criteria provided, single submitter	clinical testing	MTHFR: BP4, BS1, BS2
Labcorp Genetics (formerly Invitae), Labcorp	RCV001197542	SCV001733272	benign	Homocystinuria due to methylene tetrahydrofolate reductase deficiency	2025-02-03	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV001197542	SCV001748535	benign	Homocystinuria due to methylene tetrahydrofolate reductase deficiency	2021-07-01	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University Hospital Muenster	RCV001197542	SCV002506414	benign	Homocystinuria due to methylene tetrahydrofolate reductase deficiency	2023-12-06	criteria provided, single submitter	clinical testing	ACMG categories: BA1, BP4
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000430863	SCV004099611	likely benign	not specified	2023-09-07	criteria provided, single submitter	clinical testing	Variant summary: MTHFR c.1286A>C (p.Glu429Ala) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.29 in 251462 control chromosomes in the gnomAD database, including 11567 homozygotes strongly suggesting that the variant is benign. This variant, c.1286A>C is also known as 1298A>C. One publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in >50%-90% of normal activity and homocysteine levels for heterozygotes and homozygotes were not different from those with the wild type genotype, supporting the idea that this polymorphism alone might not significantly affect homocysteine metabolism (example: Weisberg_2001). The following publication has been ascertained in the context of this evaluation (PMID: 11395038). Ten submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as Benign/likely benign (n=7), uncertain significance (n=1), risk factor (n=1) and likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as likely benign.
Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre	RCV001197542	SCV004805343	benign	Homocystinuria due to methylene tetrahydrofolate reductase deficiency	2024-03-25	criteria provided, single submitter	research
OMIM	RCV000003698	SCV000023861	benign	MTHFR THERMOLABILE POLYMORPHISM	2008-07-01	no assertion criteria provided	literature only
OMIM	RCV000003699	SCV000023862	risk factor	Schizophrenia, susceptibility to	2008-07-01	no assertion criteria provided	literature only
Department of Pharmacy and Biotechnology, University of Bologna	RCV000144922	SCV000187679	uncertain significance	Gastrointestinal stromal tumor		flagged submission	case-control
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV001197542	SCV001368321	likely pathogenic	Homocystinuria due to methylene tetrahydrofolate reductase deficiency	2019-01-28	flagged submission	clinical testing	This variant was classified as: Likely pathogenic. The following ACMG criteria were applied in classifying this variant: No criteria apply. This variant was detected in homozygous state.
Natera, Inc.	RCV001197542	SCV001455754	benign	Homocystinuria due to methylene tetrahydrofolate reductase deficiency	2020-09-16	no assertion criteria provided	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000430863	SCV001741945	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000430863	SCV001919429	benign	not specified		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000430863	SCV001928366	benign	not specified		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000430863	SCV001956936	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000430863	SCV002037998	benign	not specified		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003974792	SCV004794374	benign	MTHFR-related disorder	2023-12-01	no assertion criteria provided	clinical testing	This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).