CPN1 G178D - GET-Evidence

Curation:
Currentness:

CPN1 G178D

(CPN1 Gly178Asp)


Short summary

This rare variant (around 1% allele frequency) is hypothesized to cause carboxypeptidase N deficiency in a recessive manner, especially if combined with a more severe variant. However the findings lack statistical sigificance: only a single case study of an affected individual links this variant to causing the disease. There aren’t any follow-up in vitro studies testing whether this variant affects protein function.

Variant evidence
Computational 1

Polyphen 2 predicts “probably damaging”

Functional

No functional data

Case/Control

Insufficient data for case/control information. Notably this variant is not extremely rare — data in dbSNP shows 2-3% allele frequency.

Familial

Familial inheritance (e.g. genotype of sister) not studied in the single case report for this variant.

See Cao H et al. 2003 (12560874).

 
Clinical importance
Severity 2

regular angioedema (40 attacks per year) in case report

See Cao H et al. 2003 (12560874).

Treatability 1

Unknown treatability

Penetrance 5

Presumed high penetrance

 

Impact

Low clinical importance, Uncertain pathogenic

(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

 

Allele frequency

  • T @ chr10:101829514: 3.6% (383/10758) in EVS
  • T @ chr10:101819503: 1.6% (2/128) in GET-Evidence
  • Frequency shown in summary reports: 3.6% (383/10758)

Publications
 

Cao H, Hegele RA. DNA polymorphism and mutations in CPN1, including the genomic basis of carboxypeptidase N deficiency. J Hum Genet. 2003;48(1):20-2. PubMed PMID: 12560874.

Testing subject GM09276 from Coriell cell repositories, an index kindred with carboxypeptidase N deficiency, researchers found three variants in CPN1-G178D. Two of these, this variant and another causing a frameshift, they implicated in causing the disease in a recessive manner. They found this variant in one out of 256 control chromosomes. The authors hypothesize that this variant (G178D) causes reduced function rather than a total loss as the subject had 20% of normal enzyme activity.

They don’t report studying any other cases nor other family members, possibly those samples weren’t available. According to Coriell, GM09276 was 73 years old at time of sampling, had “Angioedema, about 40 attacks per year; urticaria on a few occasions during childhood; long-standing ragweed hay fever and asthma; proband and a sister have approximately 20% of normal carboxypeptidase N activity in serum”.

Genomes
 

 

GS19648 - var-GS19648-1100-36-ASM
het T @ chr10:101819504

 

Other external references
 

    dbSNP
  • rs61751507
    www.ncbi.nlm.nih.gov/projects/SNP/snp_ref.cgi
    GeneTests
  • GeneTests records for the CPN1 gene
    Familial Hyperaldosteronism Type 1
    11-beta-Hydroxylase-Deficient Congenital Adrenal Hyperplasia
    www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/CPN1
    PolyPhen-2
  • Score: 0.982 (probably damaging)
    Web search results (9 hits -- see all)
  • DNA polymorphism and mutations in CPN1, including the genomic ...
    DNA polymorphism and mutations in CPN1, including the genomic basis of carboxypeptidase N ... the G178D mutation had a frequency of 0.0078, suggesting that these ...
    www.ncbi.nlm.nih.gov/pubmed/12560874
  • DNA polymorphism and mutations in CPN1, including the genomic ...
    DNA polymorphism and mutations in CPN1, including the genomic basis of carboxypeptidase N deficiency. - Henian Cao, Robert A Hegele
    www.curehunter.com/public/pubmed12560874.do
  • Science Links Japan | DNA polymorphism and mutations in CPN1 ...
    DNA polymorphism and mutations in CPN1, including the genomic basis of carboxypeptidase N ... the G178D mutation had a frequency of 0.0078, suggesting that these ...
    sciencelinks.jp/j-east/article/.../000020030803A0143012.php
  • OMIM: 603103
    Cao and Hegele (2003) sequenced the CPN1 gene in genomic DNA extracted from ... substitution (G178D; 603103.0002). . 0002 CARBOXYPEPTIDASE N DEFICIENCY CPN1, GLY178ASP ...
    www.genome.jp/dbget-bin/www_bget?omim+603103
  • PubMed: 12560874
    ... DNA polymorphism and mutations in CPN1, including the genomic basis of carboxypeptidase ... the G178D mutation had a frequency of 0.0078, suggesting that these were rare ...
    www.genome.jp/dbget-bin/www_bget?pubmed+12560874
  • Lysine Carboxypeptidase :: deficiency
    DNA polymorphism and mutations in CPN1, including the genomic basis of carboxypeptidase N ... the G178D mutation had a frequency of 0.0078, suggesting that these were rare ...
    lib.bioinfo.pl/meid:180311
  • Lysine Carboxypeptidase :: genetics
    BioInfoBank Library :: Lysine Carboxypeptidase :: genetics :: Carboxypeptidase N: a ... the G178D mutation had a frequency of 0.0078, suggesting that these were rare molecular ...
    lib.bioinfo.pl/meid:187286

Other in silico analyses
 

  • NBLOSUM100 score = 4
  • GET-Evidence autoscore = 5

Edit history
 

Gene search

"GENE" or "GENE A123C":

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