KRT85 R78H - GET-Evidence

Curation:
Currentness:

KRT85 R78H

(KRT85 Arg78His)


Short summary

Presumed benign. Although this variant was implicated in causing ectodermal dysplasia in a recessive manner in two Pakistani families (one of which was large and consanguineous), GET-Evidence reports that the variant has been seen in 5 out of 114 random control chromosomes. This strongly contradicts a severe pathogenic effect.

Variant evidence
Computational -1

Polyphen 2 predicts a damaging effect

Functional -
Case/Control 4

Presence in 5 out of 114 random controls

See unpublished research (below).

Familial -1

Very high LOD in two families, but of same ethnicity.

See Naeem M et al. 2006 (16525032), Shimomura Y et al. 2010 (19865094).

 
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

recessive

Summary of published research, and additional commentary

If the Shimomura et al. paper is treated as a screen, this represents (counting homozygous recessive individuals) case+: 1 and case-: 1. Adding the Naeem et al control+: 0, control-: 200, this has a significance of p = 0.0099 and a very high OR.

GET-Evidence finds of 5 out of 114 random control chromosomes have this variant, predicting that at least 0.2% of the population is homozygous for this variant. This is much higher than the incidence of ectodermal dysplasia, which may be around .02-.01% (1 or 2 in 10,000), significantly contradicting a severe pathogenic effect.

Allele frequency

  • T @ chr12:52760957: 4.2% (456/10738) in EVS
  • T @ chr12:51047223: 4.4% (5/114) in GET-Evidence
  • Frequency shown in summary reports: 4.2% (456/10738)

Publications
 

Naeem M, Wajid M, Lee K, Leal SM, Ahmad W. A mutation in the hair matrix and cuticle keratin KRTHB5 gene causes ectodermal dysplasia of hair and nail type. J Med Genet. 2006 Mar;43(3):274-9. PubMed PMID: 16525032; PubMed Central PMCID: PMC2563238.

This variant was implicated in ectodermal dysplasia in a large consanguineous Pakistani family. Eight affected individuals along with 12 asymptomatic were mapped for a multipoint LOD score of 8.2 and a two point of 4.54 for the 15.0 Mb region. This variant was found in all affected individuals and not seen in 200 control chromosomes.

Shimomura Y, Wajid M, Kurban M, Sato N, Christiano AM. Mutations in the keratin 85 (KRT85/hHb5) gene underlie pure hair and nail ectodermal dysplasia. J Invest Dermatol. 2010 Mar;130(3):892-5. Epub 2009 Oct 29. PubMed PMID: 19865094.

This variant was seen in Family B, only the proband was genotyped and was seen to be homozygous for this variant. (The authors mention Naeem et al.) 100 matched controls do not carry the mutation.

Genomes
 

hu04FD18 - CGI sample GS00253-DNA_F01_200_37
het T @ chr12:52760957

 

hu2D6140 - CGI sample GS01173-DNA_F06 from PGP sample 64191565
het T @ chr12:52760957

 

huAE6220 - CGI sample GS00253-DNA_H01_200_37
het T @ chr12:52760957

 

huBAAC98 - CGI sample GS01173-DNA_F02 from PGP sample 70008981
het T @ chr12:52760957

 

GS18517 - var-GS18517-1100-36-ASM
het T @ chr12:51047224

 

Other external references
 

    dbSNP
  • rs61630004
    www.ncbi.nlm.nih.gov/projects/SNP/snp_ref.cgi
    PolyPhen-2
  • Score: 0.99 (probably damaging)
    Web search results (5 hits -- see all)
  • A mutation in the hair matrix and cuticle keratin KRTHB5 gene ...
    In an effort to understand the molecular bases of this form of ectodermal ... substitution of a conserved arginine residue (R78H) located in the head domain. ...
    www.ncbi.nlm.nih.gov/pubmed/16525032
  • Keratin, type II cuticular Hb5 - Homo sapiens (Human)
    Defects in KRT85 are the cause of ectodermal dysplasia pure hair-nail ... dbSNP rs61630004. Ref.3. VAR_029657. Natural variant. 155. 1. W L: dbSNP ...
    www.uniprot.org/uniprot/P78386
  • KRT85 Gene - GeneCards | KRT85 Protein | KRT85 Antibody
    EntrezGene summary for KRT85: The protein encoded by this gene is a member of the keratin ... KRT85 Gene in genomic location: bands according to Ensembl, locations ...
    www.genecards.org/cgi-bin/carddisp.pl?gene=KRT85&snp=45
  • A mutation in the hair matrix and cuticle keratin KRTHB5 gene ...
    BACKGROUND: Ectodermal dysplasias are developmental disorders affecting tissues of ectodermal origin. ... of a conserved arginine residue (R78H) located in the head domain. ...
    www.medscape.com/medline/abstract/16525032
  • UniProt: P78386
    CC -!- DISEASE: Defects in KRT85 are the cause of ectodermal dysplasia CC pure ... GeneCards; GC12M051041; -. DR H-InvDB; HIX0036866; -. DR HGNC; HGNC:6462; KRT85. ...
    www.genome.jp/dbget-bin/www_bget?uniprot:P78386

Other in silico analyses
 

  • NBLOSUM100 score = 1
  • GET-Evidence autoscore = 4

Edit history
 

Gene search

"GENE" or "GENE A123C":

Log in