UniProtKB/Swiss-Prot O15553: Variant p.Met694Val

Pyrin
Gene: MEFV
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Variant information Variant position:

694 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 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
Variant description:

In ARFMF and ADFMF; very common mutation particularly in North African Jews; probable risk factor for amyloidosis development; reduced interaction with CASP1 and with ULK1 and diminished NLRP3 degradation after induction of autophagy by starvation (PubMed:16785446) (PubMed:26347139); effect on autophagic NLRP3 degradation is increased when associated in cis with I-680; no effect on interaction with CASP1, CASP5, NLRP1, NLRP2 or NLRP3 (PubMed:17431422). Any additional useful information about the variant.
Other resources:

Links to websites of interest for the variant.

Variant rs61752717 [ dbSNP | Ensembl ]

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.

Type	Positions	Description
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; 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; 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; 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; TRP-196; LYS-230; VAL-247; LEU-283; ARG-304; ALA-632; ILE-680; ILE-694; VAL-694; ARG-695; ALA-726; SER-744 AND HIS-761; VARIANT GLN-202;

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.