SCNN1G E197K - GET-Evidence

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SCNN1G E197K

(SCNN1G Glu197Lys)


You are viewing an old version of this page that was saved on May 31, 2011 at 3:08pm by Madeleine Ball.

Short summary

 

Variant evidence
Computational -1

Polyphen 2 predicts benign

Functional -1

Does not significantly affect sodium transport by ENaC complex

See Azad AK et al. 2009 (19462466).

Case/Control 3

Combining data from Fajac et al. & Azad et al. seems to indicate significance, although there is the risk of publication bias.

See Fajac I et al. 2008 (18507830), Azad AK et al. 2009 (19462466), unpublished research (below).

Familial

No familial data.

 
Clinical importance
Severity 4

Cystic fibrosis-like disease

Treatability 1
Penetrance 1

Rough estimate of penetrance based on combined data, assuming .02% prevalence for the disease

See Fajac I et al. 2008 (18507830), Azad AK et al. 2009 (19462466), unpublished research (below).

 

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

dominant

Summary of published research, and additional commentary

Combined data from Fajac et al. & Azad et al.:
case+: 2 + 2 = 4
case-: 53 + 74 = 127
control+: 0 + 0 + 4 = 4
control-: 50 + 176 + 643 = 869

Estimating penetrance from these numbers alone and assuming a 1 in 5,000 prevalence, increased attributable risk is .11% (total risk of .13%). Two-tailed Fisher’s exact for these combined numbers is p=.0127.

Allele frequency

  • A @ chr16:23200963: 0.6% (69/10758) in EVS
  • A @ chr16:23108463: 0.8% (1/128) in GET-Evidence
  • Frequency shown in summary reports: 0.6% (69/10758)

Publications
 

Fajac I, Viel M, Sublemontier S, Hubert D, Bienvenu T. Could a defective epithelial sodium channel lead to bronchiectasis. Respir Res. 2008 May 28;9:46. PubMed PMID: 18507830; PubMed Central PMCID: PMC2435537.

ENaC subunits beta (SCNN1B) and gamma (SCNN1G) genes in 55 patients with idiopathic bronchiectasis that also lacked homozygous or compound het CFTR mutations.
Group 1 (38 patients) had sweat chloride concentration or abnormal nasal potential differences, group 2 (17 patients) were normal in both respects. Two of the group 2 patients carried the E197K variant heterozygously, and no CFTR variants. The variant was not seen in 50 ethnically matched controls.

These two were among the most severely affected in that group on pulmonary obstruction testing. The authors do not seem to conclude high penetrance for the variant, but believe it to be associated, as they conclude: “it strengthens our hypothesis that airway disease related to partly defective ENaC protein might be the result of complex susceptibility factors.”.

Edited in this revision:

Azad AK, Rauh R, Vermeulen F, Jaspers M, Korbmacher J, Boissier B, Bassinet L, Fichou Y, des Georges M, Stanke F, De Boeck K, Dupont L, Balascáková M, Hjelte L, Lebecque P, Radojkovic D, Castellani C, Schwartz M, Stuhrmann M, Schwarz M, Skalicka V, de Monestrol I, Girodon E, Férec C, Claustres M, Tümmler B, Cassiman JJ, Korbmacher C, Cuppens H. Mutations in the amiloride-sensitive epithelial sodium channel in patients with cystic fibrosis-like disease. Hum Mutat. 2009 Jul;30(7):1093-103. PubMed PMID: 19462466.

The authors studied SCNN1A, B, & G subunits for mutations in patients with cystic-fibrosis-like disease. In 76 patients there were 2 heterozygous for this variant. 0 out of 176 healthy controls had the variant, and 4 out of 647 controls already diagnosed with cystic fibrosis (two CFTR mutations).

The authors combine SCNN1A, B, & G variants with <2.5% minor allele frequency and find 30% of cases are carriers, while only 9% of controls. We can use this combined data to make an extremely rough estimate of penetrance: assuming an incidence of 1 in 5,000 for cystic-fibrosis-like disease (.02%), carriers of one of these variants has a .05% attributable increased risk (total risk of .07%).

Genomes
 

huBEDA0B - CGI sample GS00253-DNA_C01_200_37
het A @ chr16:23200963

 

Other external references
 

    dbSNP
  • rs5738
    www.ncbi.nlm.nih.gov/projects/SNP/snp_ref.cgi
    PolyPhen-2
  • Score: 0 (benign)
    Web search results (1 hit -- see all)
  • OMIM: 600761
    Guan et al. (2005) concluded that SCNN1G is a PPARG target gene in the collecting duct ... of the SCNN1G gene, resulting in a glu197-to-lys (E197K) substitution. ...
    www.genome.jp/dbget-bin/www_bget?mim:600761

Other in silico analyses
 

  • NBLOSUM100 score = 0
  • GET-Evidence autoscore = 4

Edit history
 

Gene search

"GENE" or "GENE A123C":

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