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UniProtKB/Swiss-Prot Q99836: Variant p.Arg196Cys

Myeloid differentiation primary response protein MyD88
Gene: MYD88
Chromosomal location: 3p22
Variant information

Variant position:  196
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 Arginine (R) to Cysteine (C) at position 196 (R196C, p.Arg196Cys).
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 (C)
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

Involvement in disease:  MYD88 deficiency (MYD88D) [MIM:612260]: Patients suffer from autosomal recessive, life-threatening, often recurrent pyogenic bacterial infections, including invasive pneumococcal disease, and die between 1 and 11 months of age. Surviving patients are otherwise healthy, with normal resistance to other microbes, and their clinical status improved with age. {ECO:0000269|PubMed:18669862, ECO:0000269|PubMed:19506249, ECO:0000269|PubMed:21057262, ECO:0000269|PubMed:24316379}. 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 MYD88D; results in a loss of function; decreases NF-kappa-B complex activation.
Any additional useful information about the variant.



Sequence information

Variant position:  196
The position of the amino-acid change on the UniProtKB canonical protein sequence.

Protein sequence length:  296
The length of the canonical sequence.

Location on the sequence:   QEMIRQLEQTNYRLKLCVSD  R DVLPGTCVWSIASELIEKRC
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                         QEMIRQLEQTNYRLKLCVSDRDVLPGTCVWSIASELIEKRC

Gorilla                       QEMIRQLEQTNYRLKLCVSDRDVLPGTCVWSIASELIEKRC

Rhesus macaque                QEMIRQLEQTNYRLKLCVSDRDVLPGTCVWSIASELIEKRC

Chimpanzee                    QEMIRQLEQTNYRLKLCVSDRDVLPGTCVWSIASELIEKRC

Mouse                         QEMIRQLEQTDYRLKLCVSDRDVLPGTCVWSIASELIEKRC

Rat                           QEMIRQLEQTDYRLKLCVSDRDVLPGTCVWSIASELIEKRC

Pig                           QEMIRQLEQTNYRLKLCVSDRDVLPGTCVWSIASELIEKRC

Bovine                        HEMIRQLEQTNYRLKLCVSDRDVLPGTCVWSIASELIEKRC

Sheep                         HEMIRQLEQTNYRLKLCVSDRDVLPGTCVWSIASELIEKRC

Chicken                       QEMIRELEQTEFKLKLCVFDRDVLPGTCVWSISGELIERRC

Xenopus tropicalis            QEMISRLEQTDYKLKLCVFDRDVLPGTCLWSITSELIEHRC

Zebrafish                     HEMIKQLEHTEYNLKLCVFDRDVLPGTCVWTIASELIEKRC

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 – 296 Myeloid differentiation primary response protein MyD88
Domain 159 – 296 TIR
Alternative sequence 156 – 296 HMPERFDAFICYCPSDIQFVQEMIRQLEQTNYRLKLCVSDRDVLPGTCVWSIASELIEKRCRRMVVVVSDDYLQSKECDFQTKFALSLSPGAHQKRLIPIKYKAMKKEFPSILRFITVCDYTNPCTKSWFWTRLAKALSLP -> AAGWWWLSLMITCRARNVTSRPNLHSASLQVPIRSD. In isoform 3 and isoform 4.
Alternative sequence 215 – 215 R -> RLARRPRGG. In isoform 6.
Mutagenesis 196 – 196 R -> A. Reduced interaction with TIRAP, and strongly reduced activity. Strongly reduced interaction with TIRAP; when associated with A-288.
Mutagenesis 197 – 197 D -> A. Slightly reduced activity.
Helix 196 – 198


Literature citations

Functional assessment of the mutational effects of human IRAK4 and MyD88 genes.
Yamamoto T.; Tsutsumi N.; Tochio H.; Ohnishi H.; Kubota K.; Kato Z.; Shirakawa M.; Kondo N.;
Mol. Immunol. 58:66-76(2014)
Cited for: FUNCTION; INTERACTION WITH IRAK4; CHARACTERIZATION OF VARIANTS TYR-34; CYS-98 AND ILE-178; CHARACTERIZATION OF VARIANTS MYD88D GLU-52 DEL; PRO-93 AND CYS-196;

Structural basis for the multiple interactions of the MyD88 TIR domain in TLR4 signaling.
Ohnishi H.; Tochio H.; Kato Z.; Orii K.E.; Li A.; Kimura T.; Hiroaki H.; Kondo N.; Shirakawa M.;
Proc. Natl. Acad. Sci. U.S.A. 106:10260-10265(2009)
Cited for: STRUCTURE BY NMR OF 148-296; FUNCTION; INTERACTION WITH TIRAP AND IRAK4; MUTAGENESIS OF ARG-196; ASP-197; ARG-217; LYS-282 AND ARG-288; CHARACTERIZATION OF VARIANT MYD88D CYS-196;

Pyogenic bacterial infections in humans with MyD88 deficiency.
von Bernuth H.; Picard C.; Jin Z.; Pankla R.; Xiao H.; Ku C.-L.; Chrabieh M.; Mustapha I.B.; Ghandil P.; Camcioglu Y.; Vasconcelos J.; Sirvent N.; Guedes M.; Vitor A.B.; Herrero-Mata M.J.; Arostegui J.I.; Rodrigo C.; Alsina L.; Ruiz-Ortiz E.; Juan M.; Fortuny C.; Yaguee J.; Anton J.; Pascal M.; Chang H.-H.; Janniere L.; Rose Y.; Garty B.-Z.; Chapel H.; Issekutz A.; Marodi L.; Rodriguez-Gallego C.; Banchereau J.; Abel L.; Li X.; Chaussabel D.; Puel A.; Casanova J.-L.;
Science 321:691-696(2008)
Cited for: VARIANTS MYD88D PRO-93 AND CYS-196; CHARACTERIZATION OF VARIANTS MYD88D PRO-93 AND CYS-196;

Clinical features and outcome of patients with IRAK-4 and MyD88 deficiency.
Picard C.; von Bernuth H.; Ghandil P.; Chrabieh M.; Levy O.; Arkwright P.D.; McDonald D.; Geha R.S.; Takada H.; Krause J.C.; Creech C.B.; Ku C.L.; Ehl S.; Marodi L.; Al-Muhsen S.; Al-Hajjar S.; Al-Ghonaium A.; Day-Good N.K.; Holland S.M.; Gallin J.I.; Chapel H.; Speert D.P.; Rodriguez-Gallego C.; Colino E.; Garty B.Z.; Roifman C.; Hara T.; Yoshikawa H.; Nonoyama S.; Domachowske J.; Issekutz A.C.; Tang M.; Smart J.; Zitnik S.E.; Hoarau C.; Kumararatne D.S.; Thrasher A.J.; Davies E.G.; Bethune C.; Sirvent N.; de Ricaud D.; Camcioglu Y.; Vasconcelos J.; Guedes M.; Vitor A.B.; Rodrigo C.; Almazan F.; Mendez M.; Arostegui J.I.; Alsina L.; Fortuny C.; Reichenbach J.; Verbsky J.W.; Bossuyt X.; Doffinger R.; Abel L.; Puel A.; Casanova J.L.;
Medicine (Baltimore) 89:403-425(2010)
Cited for: INVOLVEMENT IN MYD88D; VARIANTS MYD88D GLU-52 DEL; PRO-93 AND CYS-196;

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.