rs2066472
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM2PM5BP4BS1_Supporting
The NM_005957.5(MTHFR):c.203G>A(p.Arg68Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000731 in 1,613,930 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R68G) has been classified as Likely pathogenic.
Frequency
Consequence
NM_005957.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MTHFR | NM_005957.5 | c.203G>A | p.Arg68Gln | missense_variant | 2/12 | ENST00000376590.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MTHFR | ENST00000376590.9 | c.203G>A | p.Arg68Gln | missense_variant | 2/12 | 1 | NM_005957.5 | A1 |
Frequencies
GnomAD3 genomes ? AF: 0.000309 AC: 47AN: 152178Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000175 AC: 44AN: 251238Hom.: 0 AF XY: 0.000140 AC XY: 19AN XY: 135784
GnomAD4 exome AF: 0.0000486 AC: 71AN: 1461752Hom.: 1 Cov.: 31 AF XY: 0.0000440 AC XY: 32AN XY: 727150
GnomAD4 genome ? AF: 0.000309 AC: 47AN: 152178Hom.: 0 Cov.: 32 AF XY: 0.000404 AC XY: 30AN XY: 74326
ClinVar
Submissions by phenotype
Schizophrenia;C1856061:Homocystinuria due to methylene tetrahydrofolate reductase deficiency;C1866558:Neural tube defects, folate-sensitive;C3160733:Thrombophilia due to thrombin defect Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Mar 31, 2022 | - - |
Homocystinuria due to methylene tetrahydrofolate reductase deficiency Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Aug 19, 2022 | This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 68 of the MTHFR protein (p.Arg68Gln). This variant is present in population databases (rs2066472, gnomAD 0.1%). This variant has not been reported in the literature in individuals affected with MTHFR-related conditions. ClinVar contains an entry for this variant (Variation ID: 1445361). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant disrupts the p.Arg68 amino acid residue in MTHFR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 25736335, 27743313, 29246599). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at