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UniProtKB/Swiss-Prot P29033: Variant p.Asp66His

Gap junction beta-2 protein
Gene: GJB2
Variant information

Variant position:  66
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 Aspartate (D) to Histidine (H) at position 66 (D66H, p.Asp66His).
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 medium size and acidic (D) to medium size and polar (H)
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:  Vohwinkel syndrome (VOWNKL) [MIM:124500]: An autosomal dominant disease characterized by hyperkeratosis, constriction on fingers and toes and congenital deafness. {ECO:0000269|PubMed:10369869, ECO:0000269|PubMed:12668604, ECO:0000269|PubMed:15954104, ECO:0000269|PubMed:18688874}. 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:  Keratoderma, palmoplantar, with deafness (PPKDFN) [MIM:148350]: An autosomal dominant disorder characterized by the association of palmoplantar hyperkeratosis with progressive, bilateral, high-frequency, sensorineural deafness. {ECO:0000269|PubMed:10633135, ECO:0000269|PubMed:10757647, ECO:0000269|PubMed:12372058, ECO:0000269|PubMed:12668604, ECO:0000269|PubMed:15996214, ECO:0000269|PubMed:17993581, ECO:0000269|PubMed:9856479}. 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 VOWNKL and PPKDFN; impairs trafficking; localizes intracellularly closed to the nucleus; affects the ability to form functional channels; phenotype can be rescued by coexpression with wild-type protein.
Any additional useful information about the variant.

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



Sequence information

Variant position:  66
The position of the amino-acid change on the UniProtKB canonical protein sequence.

Protein sequence length:  226
The length of the canonical sequence.

Location on the sequence:   DEQADFVCNTLQPGCKNVCY  D HYFPISHIRLWALQLIFVST
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                         DEQADFVCNTLQPGCKNVCYDHYFPISHIRLWALQLIFVST

Gorilla                       DEQADFVCNTLQPGCKNVCYDHYFPISHIRLWALQLIFVST

Rhesus macaque                DEQADFVCNTLQPGCKNVCYDHYFPISHIRLWALQLIFVST

Mouse                         DEQADFVCNTLQPGCKNVCYDHHFPISHIRLWALQLIMVST

Rat                           DEQADFVCNTLQPGCKNVCYDHYFPISHIRLWALQLIMVST

Bovine                        DEQADFVCNTLQPGCKNVCYDHYFPISHIRLWALQLIFVST

Sheep                         DEQADFVCNTLQPGCKNVCYDHYFPISHIRLWALQLIFVST

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 – 226 Gap junction beta-2 protein
Topological domain 41 – 73 Extracellular
Metal binding 47 – 47 Calcium
Disulfide bond 53 – 180
Disulfide bond 60 – 174
Disulfide bond 64 – 169
Helix 60 – 68


Literature citations

A missense mutation in connexin26, D66H, causes mutilating keratoderma with sensorineural deafness (Vohwinkel's syndrome) in three unrelated families.
Maestrini E.; Korge B.P.; Ocana-Sierra J.; Calzolari E.; Cambiaghi S.; Scudder P.M.; Hovnanian A.; Monaco A.P.; Munro C.S.;
Hum. Mol. Genet. 8:1237-1243(1999)
Cited for: VARIANT VOWNKL HIS-66;

Connexin mutations associated with palmoplantar keratoderma and profound deafness in a single family.
Kelsell D.P.; Wilgoss A.L.; Richard G.; Stevens H.P.; Munro C.S.; Leigh I.M.;
Eur. J. Hum. Genet. 8:141-144(2000)
Cited for: VARIANT PPKDFN HIS-66;

Mutations in the gene for connexin 26 (GJB2) that cause hearing loss have a dominant negative effect on connexin 30.
Marziano N.K.; Casalotti S.O.; Portelli A.E.; Becker D.L.; Forge A.;
Hum. Mol. Genet. 12:805-812(2003)
Cited for: CHARACTERIZATION OF VARIANTS DFNA3A SER-44 AND TRP-75; CHARACTERIZATION OF VARIANT PPKDFN ALA-59; CHARACTERIZATION OF VARIANT VOWNKL HIS-66;

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.