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UniProtKB/Swiss-Prot P11586: Variant p.Arg653Gln

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

Variant position:  653
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 Arginine (R) to Glutamine (Q) at position 653 (R653Q, p.Arg653Gln).
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:  Change from large size and basic (R) to medium size and polar (Q)
The physico-chemical property of the reference and variant residues and the change implicated.

BLOSUM score:  1
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 NTDFS; associated with disease susceptibility; increases risk for congenital heart defects; decreases enzyme stability.
Any additional useful information about the variant.

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



Sequence information

Variant position:  653
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:   FVHAGPFANIAHGNSSIIAD  R IALKLVGPEGFVVTEAGFGA
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                         FVHAGPFANIAHGNSSIIADRIALKLVGPE---------GFVVTEAGFGA

Mouse                         FVHAGPFANIAHGNSSIIADRIALKLVGPE---------GF

Rat                           FVHAGPFANIAHGNSSIIADRIALKLVGPE---------GF

Drosophila                    LVHAGPFANIAHGCNSIIADEVGLKLVGKN---------GF

Baker's yeast                 LVHAGPFANISIGASSVIADRVALKLVGTE--PEAKTEAGY

Fission yeast                 LVHAGPFANISIGASSILADRIALKLAGTEVDEDAKKEAGY

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 306 – 935 Formyltetrahydrofolate synthetase


Literature citations

Complete sequencing and characterization of 21,243 full-length human cDNAs.
Ota T.; Suzuki Y.; Nishikawa T.; Otsuki T.; Sugiyama T.; Irie R.; Wakamatsu A.; Hayashi K.; Sato H.; Nagai K.; Kimura K.; Makita H.; Sekine M.; Obayashi M.; Nishi T.; Shibahara T.; Tanaka T.; Ishii S.; Yamamoto J.; Saito K.; Kawai Y.; Isono Y.; Nakamura Y.; Nagahari K.; Murakami K.; Yasuda T.; Iwayanagi T.; Wagatsuma M.; Shiratori A.; Sudo H.; Hosoiri T.; Kaku Y.; Kodaira H.; Kondo H.; Sugawara M.; Takahashi M.; Kanda K.; Yokoi T.; Furuya T.; Kikkawa E.; Omura Y.; Abe K.; Kamihara K.; Katsuta N.; Sato K.; Tanikawa M.; Yamazaki M.; Ninomiya K.; Ishibashi T.; Yamashita H.; Murakawa K.; Fujimori K.; Tanai H.; Kimata M.; Watanabe M.; Hiraoka S.; Chiba Y.; Ishida S.; Ono Y.; Takiguchi S.; Watanabe S.; Yosida M.; Hotuta T.; Kusano J.; Kanehori K.; Takahashi-Fujii A.; Hara H.; Tanase T.-O.; Nomura Y.; Togiya S.; Komai F.; Hara R.; Takeuchi K.; Arita M.; Imose N.; Musashino K.; Yuuki H.; Oshima A.; Sasaki N.; Aotsuka S.; Yoshikawa Y.; Matsunawa H.; Ichihara T.; Shiohata N.; Sano S.; Moriya S.; Momiyama H.; Satoh N.; Takami S.; Terashima Y.; Suzuki O.; Nakagawa S.; Senoh A.; Mizoguchi H.; Goto Y.; Shimizu F.; Wakebe H.; Hishigaki H.; Watanabe T.; Sugiyama A.; Takemoto M.; Kawakami B.; Yamazaki M.; Watanabe K.; Kumagai A.; Itakura S.; Fukuzumi Y.; Fujimori Y.; Komiyama M.; Tashiro H.; Tanigami A.; Fujiwara T.; Ono T.; Yamada K.; Fujii Y.; Ozaki K.; Hirao M.; Ohmori Y.; Kawabata A.; Hikiji T.; Kobatake N.; Inagaki H.; Ikema Y.; Okamoto S.; Okitani R.; Kawakami T.; Noguchi S.; Itoh T.; Shigeta K.; Senba T.; Matsumura K.; Nakajima Y.; Mizuno T.; Morinaga M.; Sasaki M.; Togashi T.; Oyama M.; Hata H.; Watanabe M.; Komatsu T.; Mizushima-Sugano J.; Satoh T.; Shirai Y.; Takahashi Y.; Nakagawa K.; Okumura K.; Nagase T.; Nomura N.; Kikuchi H.; Masuho Y.; Yamashita R.; Nakai K.; Yada T.; Nakamura Y.; Ohara O.; Isogai T.; Sugano S.;
Nat. Genet. 36:40-45(2004)
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]; VARIANTS ARG-134 AND GLN-653;

Submission
Mural R.J.; Istrail S.; Sutton G.G.; Florea L.; Halpern A.L.; Mobarry C.M.; Lippert R.; Walenz B.; Shatkay H.; Dew I.; Miller J.R.; Flanigan M.J.; Edwards N.J.; Bolanos R.; Fasulo D.; Halldorsson B.V.; Hannenhalli S.; Turner R.; Yooseph S.; Lu F.; Nusskern D.R.; Shue B.C.; Zheng X.H.; Zhong F.; Delcher A.L.; Huson D.H.; Kravitz S.A.; Mouchard L.; Reinert K.; Remington K.A.; Clark A.G.; Waterman M.S.; Eichler E.E.; Adams M.D.; Hunkapiller M.W.; Myers E.W.; Venter J.C.;
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]; VARIANTS ARG-134 AND GLN-653;

The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC).
The MGC Project Team;
Genome Res. 14:2121-2127(2004)
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]; VARIANTS ARG-134; GLN-653 AND PHE-769;

Molecular genetic analysis of the gene encoding the trifunctional enzyme MTHFD (methylenetetrahydrofolate-dehydrogenase, methenyltetrahydrofolate-cyclohydrolase, formyltetrahydrofolate synthetase) in patients with neural tube defects.
Hol F.A.; van der Put N.M.J.; Geurds M.P.A.; Heil S.G.; Trijbels F.J.M.; Hamel B.C.J.; Mariman E.C.M.; Blom H.J.;
Clin. Genet. 53:119-125(1998)
Cited for: INVOLVEMENT IN SUSCEPTIBILITY TO NTDFS; VARIANTS NTDFS HIS-293 AND GLN-653;

A polymorphism, R653Q, in the trifunctional enzyme methylenetetrahydrofolate dehydrogenase/methenyltetrahydrofolate cyclohydrolase/formyltetrahydrofolate synthetase is a maternal genetic risk factor for neural tube defects: report of the Birth Defects Research Group.
Brody L.C.; Conley M.; Cox C.; Kirke P.N.; McKeever M.P.; Mills J.L.; Molloy A.M.; O'Leary V.B.; Parle-McDermott A.; Scott J.M.; Swanson D.A.;
Am. J. Hum. Genet. 71:1207-1215(2002)
Cited for: INVOLVEMENT IN SUSCEPTIBILITY TO NTDFS; VARIANT NTDFS GLN-653;

Confirmation of the R653Q polymorphism of the trifunctional C1-synthase enzyme as a maternal risk for neural tube defects in the Irish population.
Parle-McDermott A.; Kirke P.N.; Mills J.L.; Molloy A.M.; Cox C.; O'Leary V.B.; Pangilinan F.; Conley M.; Cleary L.; Brody L.C.; Scott J.M.;
Eur. J. Hum. Genet. 14:768-772(2006)
Cited for: INVOLVEMENT IN SUSCEPTIBILITY TO NTDFS; VARIANT NTDFS GLN-653;

The MTHFD1 p.Arg653Gln variant alters enzyme function and increases risk for congenital heart defects.
Christensen K.E.; Rohlicek C.V.; Andelfinger G.U.; Michaud J.; Bigras J.-L.; Richter A.; Mackenzie R.E.; Rozen R.;
Hum. Mutat. 30:212-220(2009)
Cited for: CHARACTERIZATION OF VARIANT GLN-653; ASSOCIATION WITH RISK OF CONGENITAL HEART DEFECTS;

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.