GJB3 R32W - GET-Evidence

Curation:
Currentness:

GJB3 R32W

(GJB3 Arg32Trp)


Short summary

Probably benign. Although Polyphen 2 predicts it be damaging and some publications suggested it might have a functional effect, others report it to be a fairly common polymorphism and functional studies failed to find a difference between it and wild type.

Variant evidence
Computational -1

Polyphen 2 predicts damaging effect

Functional 1

no functional differences from wildtype seen.

See Rouan F et al. 2003 (12702148).

Case/Control 4

Frequencies in controls strongly contradict any significant pathogenic effect.

See 11175305.

Familial -
 
Clinical importance
Severity -
Treatability -
Penetrance -
 

Impact

Low clinical importance, Uncertain benign

(The "low clinical importance, uncertain" qualifier is assigned automatically based on the above evidence and importance scores.)

Inheritance pattern

unknown

Summary of published research, and additional commentary

 

Allele frequency

  • T @ chr1:35250457: 2.2% (240/10758) in EVS
  • T @ chr1:35023043: 1.6% (2/128) in GET-Evidence
  • Frequency shown in summary reports: 2.2% (240/10758)

Publications
 

Kelsell DP, Wilgoss AL, Richard G, Stevens HP, Munro CS, Leigh IM. Connexin mutations associated with palmoplantar keratoderma and profound deafness in a single family. Eur J Hum Genet. 2000 Jun;8(6):469-72. PubMed PMID: 10888284.

This variant was found in a family previously studied with deafness (of varying degrees) and palmoplantar keratoderma. Previously, GJB2-M34T was implicated, but other publications argued it was a nonpathogenic polymorphism, as normal-hearing carriers have been reported. The authors extend their examination of this family and find two other mutations which they suggest may have contributed to a pathogenic effect of the GJB2-M24T variant: GJB2-D66H and this variant, GJB3-R32W. They report seeing R32W in two individuals in the pedigree, and report screening 244 control chromosomes (equivalent to 122 individuals) and finding it in one unaffected individual.

López-Bigas N, Rabionet R, Arbonés ML, Estivill X. R32W variant in Connexin 31: mutation or polymorphism for deafness and skin disease? Eur J Hum Genet. 2001 Jan;9(1):70. PubMed PMID: 11175305.

These authors follow up on the findings of Kelsell et al. and report finding the variant in 7 out of 153 individuals with hearing loss and in 8 out of 46 control subjects with no obvious skin disorder or hearing impairment. They conclude the variant is a common polymorphism in the Spanish population (3.8% allele frequency).

Rouan F, Lo CW, Fertala A, Wahl M, Jost M, Rodeck U, Uitto J, Richard G. Divergent effects of two sequence variants of GJB3 (G12D and R32W) on the function of connexin 31 in vitro. Exp Dermatol. 2003 Apr;12(2):191-7. PubMed PMID: 12702148.

This group finds that the G12D variant in this gene was functionally impacted, failing to form functional gap junction channels, while this variant (R32W) was comparable to wild type, supporting interpretation of R32W as a functionally inconsequential polymorphism.

Genomes
 

 

GS19648 - var-GS19648-1100-36-ASM
het T @ chr1:35023044

 

Other external references
 

    dbSNP
  • rs1805063
    www.ncbi.nlm.nih.gov/projects/SNP/snp_ref.cgi
    PolyPhen-2
  • Score: 1.0 (probably damaging)

Other in silico analyses
 

  • NBLOSUM100 score = 7
  • GET-Evidence autoscore = 4

Edit history
 

Gene search

"GENE" or "GENE A123C":

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