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UniProtKB/Swiss-Prot O15553: Variant p.Met680Ile

Pyrin
Gene: MEFV
Variant information

Variant position:  680
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 Methionine (M) to Isoleucine (I) at position 680 (M680I, p.Met680Ile).
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:  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

Involvement in disease:  Familial Mediterranean fever, autosomal dominant (ADFMF) [MIM:134610]: A hereditary periodic fever syndrome characterized by periodic fever, serosal inflammation and pain in the abdomen, chest or joints as seen also in the autosomal recessive form of the disease. It is associated with reactive renal amyloidosis and characterized by colchicine unresponsiveness. {ECO:0000269|PubMed:10787449, ECO:0000269|PubMed:14679589}. 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.

Involvement in disease:  Familial Mediterranean fever, autosomal recessive (ARFMF) [MIM:249100]: A hereditary periodic fever syndrome characterized by recurrent episodic fever, serosal inflammation and pain in the abdomen, chest or joints. It is frequently complicated by reactive amyloidosis, which leads to renal failure and can be prophylactically treated with colchicine. {ECO:0000269|PubMed:10024914, ECO:0000269|PubMed:10090880, ECO:0000269|PubMed:10234504, ECO:0000269|PubMed:10364520, ECO:0000269|PubMed:10612841, ECO:0000269|PubMed:10842288, ECO:0000269|PubMed:10854105, ECO:0000269|PubMed:11470495, ECO:0000269|PubMed:15024744, ECO:0000269|PubMed:16378925, ECO:0000269|PubMed:16730661, ECO:0000269|PubMed:23031807, ECO:0000269|PubMed:24929125, ECO:0000269|PubMed:26347139, ECO:0000269|PubMed:9288094, ECO:0000269|PubMed:9288758, ECO:0000269|PubMed:9668175}. Note=The disease is caused by mutations affecting the gene represented in this entry. The disease-associated mutations in the B30.2/SPRY domain perturb ULK1 recruitment and autophagic degradation of inflammasome components, including NLRP3, and hence may contribute to the inflammatory phenotype associated with ARFMF. {ECO:0000269|PubMed:26347139}.
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 arFMF and adFMF; reduced CASP1 interaction; decreased interaction with ULK1 and diminished NLRP3 degradation after induction of autophagy by starvation; when associated with V-694 (PubMed:26347139).
Any additional useful information about the variant.

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



Sequence information

Variant position:  680
The position of the amino-acid change on the UniProtKB canonical protein sequence.

Protein sequence length:  781
The length of the canonical sequence.

Location on the sequence:   GDKTAWILGACKTSISRKGN  M TLSPENGYWVVIMMKENEYQ
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                         GDKTAWILGACKTSISRKGNMTLSPENGYWVVIMMKENEYQ

Mouse                         QGLVPTVHLKCDGAHTQDCDVVFYP-------------ERE

Rat                           QALIPTVHLKCDGAHTQDFDVILCA-------------ELE

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 – 781 Pyrin
Domain 580 – 775 B30.2/SPRY
Alternative sequence 587 – 781 VPELIGAQAHAVNVILDAETAYPNLIFSDDLKSVRLGNKWERLPDGPQRFDSCIIVLGSPSFLSGRRYWEVEVGDKTAWILGACKTSISRKGNMTLSPENGYWVVIMMKENEYQASSVPPTRLLIKEPPKRVGIFVDYRVGSISFYNVTARSHIYTFASCSFSGPLQPIFSPGTRDGGKNTAPLTICPVGGQGPD -> DHSPQHGLGSWEERDYTQHSMQGPKQGVPCLSLLSGQCNLAPLNANAQDFFPYLIFLRSSGADWRSGTCC. In isoform 3.


Literature citations

Ancient missense mutations in a new member of the RoRet gene family are likely to cause familial Mediterranean fever.
Aksentijevich I.; Centola M.; Deng Z.; Sood R.; Balow J.E. Jr.; Wood G.; Zaks N.; Mansfield E.; Chen X.; Eisenberg S.; Vedula A.; Shafran N.; Raben N.; Pras E.; Pras M.; Kastner D.L.; Blake T.; Baxevanis A.D.; Robbins C.; Krizman D.; Collins F.S.; Liu P.P.; Chen X.; Shohat M.; Hamon M.; Kahan T.; Cercek A.; Rotter J.I.; Fischel-Ghodsian N.; Richards N.; Shelton D.A.; Gumucio D.; Yokoyama Y.; Mangelsdorf M.; Orsborn A.; Richards R.I.; Ricke D.O.; Buckingham J.M.; Moyzis R.K.; Deaven L.L.; Doggett N.A.;
Cell 90:797-807(1997)
Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1); VARIANTS ARFMF ILE-680; VAL-694 AND ALA-726;

A candidate gene for familial Mediterranean fever.
Bernot A.; Clepet C.; Dasilva C.; Devaud C.; Petit J.-L.; Caloustian C.; Cruaud C.; Samson D.; Pulcini F.; Weissenbach J.; Heilig R.; Notanicola C.; Domingo C.; Rozenbaum M.; Benchetrit E.; Topaloglu R.; Dewalle M.; Dross C.; Hadjari P.; Dupont M.; Demaille J.G.; Touitou I.; Smaoui N.; Nedelec B.; Mery J.-P.; Chaabouni H.; Delpech M.; Grateau G.;
Nat. Genet. 17:25-31(1997)
Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 305-754; VARIANTS ARFMF ILE-680 AND ILE-694;

The B30.2 domain of pyrin, the familial Mediterranean fever protein, interacts directly with caspase-1 to modulate IL-1beta production.
Chae J.J.; Wood G.; Masters S.L.; Richard K.; Park G.; Smith B.J.; Kastner D.L.;
Proc. Natl. Acad. Sci. U.S.A. 103:9982-9987(2006)
Cited for: INTERACTION WITH CASP1; CHARACTERIZATION OF VARIANTS ILE-680; VAL-694 AND ALA-726;

TRIM-mediated precision autophagy targets cytoplasmic regulators of innate immunity.
Kimura T.; Jain A.; Choi S.W.; Mandell M.A.; Schroder K.; Johansen T.; Deretic V.;
J. Cell Biol. 210:973-989(2015)
Cited for: FUNCTION; INTERACTION WITH ATG16L1; BECN1; GABARAP; GABARAPL1; GABARAPL2; MAP1LC3A; MAP1LC3C; NLRP3; TRIM21 AND ULK1; SUBCELLULAR LOCATION; INDUCTION BY IFNG; DEGRADATION BY AUTOPHAGY; CHARACTERIZATION OF VARIANTS ARFMF ILE-680; VAL-694 AND ALA-726; MUTAGENESIS OF 397-ILE--HIS-404; 470-TYR--GLY-488 AND 523-SER--ASP-530;

Pyrin/marenostrin mutations in familial Mediterranean fever.
Booth D.R.; Gillmore J.D.; Booth S.E.; Pepys M.B.; Hawkins P.N.;
QJM 91:603-606(1998)
Cited for: VARIANTS ARFMF ILE-680; ILE-681; ILE-694; VAL-694; MET-694 DEL AND ALA-726;

MEFV-Gene analysis in Armenian patients with familial Mediterranean fever: diagnostic value and unfavorable renal prognosis of the M694V homozygous genotype-genetic and therapeutic implications.
Cazeneuve C.; Sarkisian T.; Pecheux C.; Dervichian M.; Nedelec B.; Reinert P.; Ayvazyan A.; Kouyoumdjian J.-C.; Ajrapetyan H.; Delpech M.; Goossens M.; Dode C.; Grateau G.; Amselem S.;
Am. J. Hum. Genet. 65:88-97(1999)
Cited for: VARIANTS ARFMF GLN-148; SER-369; GLN-408; LEU-479; ILE-680; VAL-694; ALA-726 AND HIS-761;

Phenotype-genotype correlation in familial Mediterranean fever: evidence for an association between Met694Val and amyloidosis.
Shohat M.; Magal N.; Shohat T.; Chen X.; Dagan T.; Mimouni A.; Danon Y.; Lotan R.; Ogur G.; Sirin A.; Schlezinger M.; Halpern G.J.; Schwabe A.; Kastner D.; Rotter J.I.; Fischel-Ghodsian N.;
Eur. J. Hum. Genet. 7:287-292(1999)
Cited for: VARIANTS ARFMF ILE-680; ILE-694; VAL-694 AND ALA-726;

MEFV mutations in Turkish patients suffering from familial Mediterranean fever.
Akar N.; Misiroglu M.; Yalcinkaya F.; Akar E.; Cakar N.; Tumer N.; Akcakus M.; Tastan H.; Matzner Y.;
Hum. Mutat. 15:118-119(2000)
Cited for: VARIANTS ARFMF GLN-148; ILE-680; ILE-694; VAL-694; ARG-695; ALA-726 AND HIS-761;

The genetic basis of autosomal dominant familial Mediterranean fever.
Booth D.R.; Gillmore J.D.; Lachmann H.J.; Booth S.E.; Bybee A.; Soytuerk M.; Akar S.; Pepys M.B.; Tunca M.; Hawkins P.N.;
QJM 93:217-221(2000)
Cited for: VARIANTS ADFMF GLN-148; ILE-680; ILE-694; MET-694 DEL AND VAL-694;

Familial Mediterranean fever (FMF) in Lebanon and Jordan: a population genetics study and report of three novel mutations.
Medlej-Hashim M.; Serre J.-L.; Corbani S.; Saab O.; Jalkh N.; Delague V.; Chouery E.; Salem N.; Loiselet J.; Lefranc G.; Megarbane A.;
Eur. J. Med. Genet. 48:412-420(2005)
Cited for: VARIANTS ARFMF ARG-108; GLN-148; VAL-148; ASP-167; ILE-177; ILE-267; LYS-474; LEU-479; HIS-653; ILE-680; ILE-694; VAL-694; ARG-695; MET-720; ALA-726; SER-744 AND HIS-761;

Frequency of MEFV gene mutations in Hatay province, Mediterranean region of Turkey and report of a novel missense mutation (I247V).
Gunesacar R.; Celik M.M.; Arica V.; Elmacioglu S.; Ozturk O.H.;
Gene 546:195-199(2014)
Cited for: VARIANTS ARFMF PRO-110; GLN-148; LYS-230; ILE-680; ILE-694; VAL-694; ARG-695; ALA-726; SER-744 AND HIS-761; VARIANTS TRP-196; GLN-202; VAL-247; LEU-283; ARG-304 AND ALA-632;

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.