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UniProtKB/Swiss-Prot P11586: Variant p.Leu51Pro

C-1-tetrahydrofolate synthase, cytoplasmic
Gene: MTHFD1
Variant information

Variant position:  51
The position of the amino-acid change on the UniProtKB canonical protein sequence.

Type of variant:  Disease [Disclaimer]
The variants are classified into three categories: Disease, Polymorphism and Unclassified.
  • Disease: Variants implicated in disease according to literature reports.
  • Polymorphism: Variants not reported to be implicated in disease.
  • Unclassified: Variants with uncertain implication in disease according to literature reports. Evidence against or in favor of a pathogenic role is limited and/or conflicting.

Residue change:  From Leucine (L) to Proline (P) at position 51 (L51P, p.Leu51Pro).
Indicates the amino acid change of the variant. The one-letter and three-letter codes for amino acids used in UniProtKB/Swiss-Prot are those adopted by the commission on Biochemical Nomenclature of the IUPAC-IUB.

Physico-chemical properties:  Similar physico-chemical property. Both residues are medium size and hydrophobic.
The physico-chemical property of the reference and variant residues and the change implicated.

BLOSUM score:  -3
The score within a Blosum matrix for the corresponding wild-type to variant amino acid change. The log-odds score measures the logarithm for the ratio of the likelihood of two amino acids appearing by chance. The Blosum62 substitution matrix is used. This substitution matrix contains scores for all possible exchanges of one amino acid with another:
  • Lowest score: -4 (low probability of substitution).
  • Highest score: 11 (high probability of substitution).
More information can be found on the following page

Involvement in disease:  Combined immunodeficiency and megaloblastic anemia with or without hyperhomocysteinemia (CIMAH) [MIM:617780]: An autosomal recessive disorder due to an inborn error of folate metabolism. Variable clinical manifestations include hemolytic uremic syndrome, macrocytosis, epilepsy, hearing loss, retinopathy, mild mental retardation, and lymphopenia. {ECO:0000269|PubMed:21813566, ECO:0000269|PubMed:25633902, ECO:0000269|PubMed:27707659}. Note=The disease is caused by mutations affecting the gene represented in this entry.
The name and a short description of the disease associated with the variant. For more information about the disease, the user can refer to OMIM, following the link provided after the disease acronym.

Variant description:  In CIMAH.
Any additional useful information about the variant.

Other resources:  
Links to websites of interest for the variant.

Sequence information

Variant position:  51
The position of the amino-acid change on the UniProtKB canonical protein sequence.

Protein sequence length:  935
The length of the canonical sequence.

The residue change on the sequence. Unless the variant is located at the beginning or at the end of the protein sequence, both residues upstream (20) and downstream (20) of the variant will be shown.

Residue conservation: 
The multiple alignment of the region surrounding the variant against various orthologous sequences.







Sequence annotation in neighborhood:  
The regions or sites of interest surrounding the variant. In general the features listed are posttranslational modifications, binding sites, enzyme active sites, local secondary structure or other characteristics reported in the cited references. The "Sequence annotation in neighborhood" lines have a fixed format:
  • Type: the type of sequence feature.
  • Positions: endpoints of the sequence feature.
  • Description: contains additional information about the feature.

Chain 1 – 935 C-1-tetrahydrofolate synthase, cytoplasmic
Chain 2 – 935 C-1-tetrahydrofolate synthase, cytoplasmic, N-terminally processed
Region 2 – 305 Methylenetetrahydrofolate dehydrogenase and cyclohydrolase
Mutagenesis 49 – 49 S -> A. No effect on dehydrogenase and cyclohydrolase activity. Strong increase of Km for NADP.
Mutagenesis 49 – 49 S -> Q. Reduces dehydrogenase by 75% and cyclohydrolase activity by 99%. No effect on Km for NADP and for 5,10-methenyltetrahydrofolate.
Mutagenesis 52 – 52 Y -> AS. Reduces dehydrogenase activity by 99%. Reduces cyclohydrolase activity by 70%. No effect on Km for NADP and for 5,10-methenyltetrahydrofolate.
Mutagenesis 52 – 52 Y -> F. Slightly reduces dehydrogenase and cyclohydrolase activity. Increase of Km for NADP and for 5,10-methenyltetrahydrofolate.
Mutagenesis 56 – 56 K -> AIST. Decreases dehydrogenase activity over 90%. Loss of cyclohydrolase activity.
Mutagenesis 56 – 56 K -> EMQ. Moderate decrease of dehydrogenase activity. Loss of cyclohydrolase activity. Strong increase of Km for NADP. Decrease of Km for 5,10-methenyltetrahydrofolate.
Mutagenesis 56 – 56 K -> R. Reduces dehydrogenase and cyclohydrolase activity by 99%. No effect on Km for NADP and for 5,10-methenyltetrahydrofolate.
Helix 47 – 63

Literature citations

Precision molecular diagnosis defines specific therapy in Combined Immunodeficiency with Megaloblastic Anemia Secondary to MTHFD1 deficiency.
Ramakrishnan K.A.; Pengelly R.J.; Gao Y.; Morgan M.; Patel S.V.; Davies E.G.; Ennis S.; Faust S.N.; Williams A.P.;
J. Allergy Clin. Immunol. Pract. 4:1160.E10-1166.E10(2016)

Disclaimer: Any medical or genetic information present in this entry is provided for research, educational and informational purposes only. They are not in any way intended to be used as a substitute for professional medical advice, diagnostic, treatment or care.