Submissions for variant NM_005957.5(MTHFR):c.1004G>A (p.Arg335His)

gnomAD frequency: 0.00004  dbSNP: rs543016186

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genetics and Prenatal Diagnosis Center, The First Affiliated Hospital of Zhengzhou University	RCV000167606	SCV001622432	pathogenic	Homocystinuria due to methylene tetrahydrofolate reductase deficiency	2021-05-13	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000167606	SCV002141559	uncertain significance	Homocystinuria due to methylene tetrahydrofolate reductase deficiency	2022-10-17	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 335 of the MTHFR protein (p.Arg335His). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with clinical features of severe methylenetetrahydrofolate reductase deficiency (PMID: 25736335, 34015165; Invitae). This variant is also known as c.1016G>A. ClinVar contains an entry for this variant (Variation ID: 187886). 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. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on MTHFR function (PMID: 27743313). This variant disrupts the p.Arg335 amino acid residue in MTHFR. Other variant(s) that disrupt this residue have been observed in individuals with MTHFR-related conditions (PMID: 7726158), which suggests that this may be a clinically significant amino acid residue. 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	RCV003468814	SCV004196392	pathogenic	Neural tube defects, folate-sensitive	2024-03-28	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004526623	SCV005039273	uncertain significance	not specified	2024-03-21	criteria provided, single submitter	clinical testing	Variant summary: MTHFR c.1004G>A (p.Arg335His) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.8e-05 in 249888 control chromosomes (gnomAD). c.1004G>A has been reported in the literature in individuals affected with clinical features of severe methylene tetrahydrofolate reductase deficiency (examples: Zhai_2021, Burda_2017). These data do not allow any conclusion about variant significance. A different variant that disrupts this residue has been classified pathogenic internally, which suggests that this may be a clinically significant amino acid residue. Experimental studies have evaluated the variant effect in vitro however, the data is inconclusive (example: Weile_2021, Burda_2017). The following publications have been ascertained in the context of this evaluation (PMID: 34015165, 34214447, 27743313, 25736335). ClinVar contains an entry for this variant (Variation ID: 187886). Based on the evidence outlined above, the variant was classified as uncertain significance.
University Children's Hospital, University of Zurich	RCV000167606	SCV000218487	pathogenic	Homocystinuria due to methylene tetrahydrofolate reductase deficiency		no assertion criteria provided	clinical testing