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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:  LP/P [Disclaimer]
The variants are classified into three categories: LP/P, LB/B and US.
  • LP/P: likely pathogenic or pathogenic.
  • LB/B: likely benign or benign.
  • US: uncertain significance

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

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.

Location on the sequence:   VPGFTPRLAILQVGNRDDSN  L YINVKLKAAEEIGIKATHIK
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.

Human                         VPGFTPRLAILQVGNRDDSNLYINVKLKAAEEIGIKATHIK

Mouse                         VPGFTPGLAILQVGDRDDSNLYINVKLKAAEEIGIKATHIK

Rat                           VPGFTPGLAILQVGDRDDSNLYINVKLKAAQEIGIKATHIK

Drosophila                    LADFVPGLRIVQVGGREDSNVYIRMKIKAATEIGIDAAHVQ

Baker's yeast                 VPGFAPNLAIIQVGNRPDSATYVRMKRKAAEEAGIVANFIH

Fission yeast                 DPYFNVSLKIIQVGGREDSNVYVRMKTRAANEAGISCEHVN

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.

TypePositionsDescription
Chain 1 – 935 C-1-tetrahydrofolate synthase, cytoplasmic
Chain 2 – 935 C-1-tetrahydrofolate synthase, cytoplasmic, N-terminally processed
Region 2 – 291 Methylenetetrahydrofolate dehydrogenase and methenyltetrahydrofolate cyclohydrolase (D/C) domain
Active site 56 – 56
Mutagenesis 49 – 49 S -> A. No effect on methylenetetrahydrofolate dehydrogenase (NADP+) activity. No effect on methenyltetrahydrofolate cyclohydrolase activity. Decreased affinity for NADP.
Mutagenesis 49 – 49 S -> Q. Reduced methylenetetrahydrofolate dehydrogenase (NADP+) activity by 75%. Reduced methenyltetrahydrofolate cyclohydrolase activity by 99%. No effect on affinity for NADP and 5,10-methenyltetrahydrofolate.
Mutagenesis 52 – 52 Y -> AS. Reduced methylenetetrahydrofolate dehydrogenase (NADP+) activity by 99%. Reduced methenyltetrahydrofolate cyclohydrolase activity by 70%. No effect on affinity for NADP and 5,10-methenyltetrahydrofolate.
Mutagenesis 52 – 52 Y -> F. Slightly reduced methylenetetrahydrofolate dehydrogenase (NADP+) activity. Slightly reduced methenyltetrahydrofolate cyclohydrolase activity. Decreased affinity for NADP and for 5,10-methenyltetrahydrofolate.
Mutagenesis 56 – 56 K -> AIST. Decreased methylenetetrahydrofolate dehydrogenase (NADP+) activity over 90%. Loss of methenyltetrahydrofolate cyclohydrolase activity.
Mutagenesis 56 – 56 K -> EMQ. Moderate decrease of methylenetetrahydrofolate dehydrogenase (NADP+) activity. Loss of methenyltetrahydrofolate cyclohydrolase activity. Strongly decreased affinity for NADP. Increased affinity for 5,10-methenyltetrahydrofolate.
Mutagenesis 56 – 56 K -> R. Reduced methylenetetrahydrofolate dehydrogenase (NADP+) activity. Reduced methenyltetrahydrofolate cyclohydrolase activity by 99%. No effect on affinity for NADP and 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)
Cited for: INVOLVEMENT IN CIMAH; VARIANT CIMAH PRO-51;

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.