UniProtKB/Swiss-Prot O15553: Variant p.Met694Val

Pyrin
Gene: MEFV
Chromosomal location: 16p13.3
Variant information

Variant position:  694
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 have been found in patients and disease-association is reported in literature. However, this classification is not a definitive assessment of variant pathogenicity.
  • Polymorphism: No disease-association has been reported.
  • Unclassified: Variants have been found in patients but disease-association remains unclear.

Residue change:  From Methionine (M) to Valine (V) at position 694 (M694V, p.Met694Val).
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. 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. 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 arFMF and adFMF; very common mutation particularly in North African Jews; can be associated with amyloidosis development; reduced interaction with CASP1 (PubMed:16785446); no effect on interaction with CASP1, CASP5, NLRP1, NLRP2 or NLRP3 (PubMed:17431422).
Any additional useful information about the variant.



Sequence information

Variant position:  694
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:   ISRKGNMTLSPENGYWVVIM  M KENEYQASSVPPTRLLIKEP
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                         ISRKGNMTLSPENGYWVVIMMKENEYQASSVPPTRLLIKEP

Mouse                         HTQDCDVVFYP-------------EREAGGSEPKDYLHPQP

Rat                           HTQDFDVILCA-------------ELEAGGSEPQDYLHPSS

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.
Beta strand 688 – 695


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;

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;

The SPRY domain of Pyrin, mutated in familial Mediterranean fever patients, interacts with inflammasome components and inhibits proIL-1beta processing.
Papin S.; Cuenin S.; Agostini L.; Martinon F.; Werner S.; Beer H.D.; Grutter C.; Grutter M.; Tschopp J.;
Cell Death Differ. 14:1457-1466(2007)
Cited for: FUNCTION; INTERACTION WITH CASP1; CASP5; NLRP1; NLRP2; NLRP3 AND IL1B; CHARACTERIZATION OF VARIANT VAL-694;

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;

Familial Mediterranean fever in the 'Chuetas' of Mallorca: a question of Jewish origin or genetic heterogeneity.
Domingo C.; Touitou I.; Bayou A.; Ozen S.; Notarnicola C.; Dewalle M.; Demaille J.; Buades R.; Sayadat C.; Levy M.; Ben-Chetrit E.;
Eur. J. Hum. Genet. 8:242-246(2000)
Cited for: VARIANTS ARFMF PRO-110; GLN-148 AND VAL-694;

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;

Mutational analysis of the PRYSPRY domain of pyrin and implications for familial mediterranean fever (FMF).
Goulielmos G.N.; Fragouli E.; Aksentijevich I.; Sidiropoulos P.; Boumpas D.T.; Eliopoulos E.;
Biochem. Biophys. Res. Commun. 345:1326-1332(2006)
Cited for: VARIANTS ARFMF SER-632; MET-640; PHE-641; LEU-646; PRO-649; HIS-653; ALA-656; ASN-661; ASN-675; GLU-678; LEU-680; ILE-681; CYS-688; ILE-694; LEU-694; VAL-694; MET-695; ARG-695; ILE-704; SER-705; MET-720; ALA-726; LEU-743; SER-744; SER-758; HIS-761 AND THR-780; VARIANT CYS-702;

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.