NKX2-5 E21Q - GET-Evidence

Curation:
Currentness:

NKX2-5 E21Q

(NKX2-5 Glu21Gln)


Short summary

Probably nonpathogenic. Reported in a single case of tetralogy of fallot (a congenital heart defect), although an unaffected mother and grandmother were also carriers. A later study also found the variant in an affected family, but the variant did not segregate with disease (other affected family members were not carriers) — they conclude that it is probably a nonpathogenic polymorphism.

Variant evidence
Computational

Polyphen 2 predicts probably damaging, but BLOSUM100 indicates Glu to Gln is not very disruptive.

Functional -
Case/Control -
Familial 1

Does not segregate with disease

See Goldmuntz E et al. 2001 (11714651), Elliott DA et al. 2003 (12798584).

 
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

undefined

Summary of published research, and additional commentary

 

Total cases/controls case+ case– control+ control– p-value odds ratio
Isolated Nonsyndromic Congenital Heart Disease/Defects
1 5 0 100 0.0566

 

Allele frequency

  • G @ chr5:172662026: 0.0% (5/10634) in EVS
  • Frequency shown in summary reports: 0.0% (5/10634)

Publications
 

Goldmuntz E, Geiger E, Benson DW. NKX2.5 mutations in patients with tetralogy of fallot. Circulation. 2001 Nov 20;104(21):2565-8. PubMed PMID: 11714651.

Seen in one of six cases of patients with tetralogy of fallot, and not seen in 100 controls. The variant was also seen in an unaffected mother and unaffected grandmother; the authors conclude that this indicates the variant has reduced penetrance. This is not very high significance: p = 0.057 using a two-tailed Fisher’s Exact test.

Cases/controls case+ case– control+ control– p-value odds ratio
Isolated Nonsyndromic Congenital Heart Disease/Defects
1 5 0 100 0.0566

 

Elliott DA, Kirk EP, Yeoh T, Chandar S, McKenzie F, Taylor P, Grossfeld P, Fatkin D, Jones O, Hayes P, Feneley M, Harvey RP. Cardiac homeobox gene NKX2-5 mutations and congenital heart disease: associations with atrial septal defect and hypoplastic left heart syndrome. J Am Coll Cardiol. 2003 Jun 4;41(11):2072-6. PubMed PMID: 12798584.

These authors found this variant in a family with atrial septal defect but no conduction disease, however, they found the variant did not segregate with disease in the family: the affected parent and grandparent were both not carriers, while a carrier sibling was unaffected. The authors conclude that this is probably a non-disease-causing polymorphism.

Genomes
 

Other external references
 

    dbSNP
  • rs104893904
    www.ncbi.nlm.nih.gov/projects/SNP/snp_ref.cgi
    PolyPhen-2
  • Score: 0.931 (probably damaging)
    Web search results (12 hits -- see all)
  • Cardiac homeobox gene NKX2-5 mutations and congenital heart ...
    Cardiac homeobox gene NKX2-5 mutations and congenital heart disease ... A second NKX2-5 amino acid change (E21Q) was identified within a family with ASD but no ...
    content.onlinejacc.org/cgi/content/full/41/11/2072
  • Cardiac homeobox gene NKX2-5 mutations and congenital heart ...
    Cardiac homeobox gene NKX2-5 mutations and congenital heart disease ... One NKX2-5 mutation-positive child from this family had HLHS, although no mutations were ...
    content.onlinejacc.org/cgi/content/abstract/41/11/2072
  • Mendelian Inheritance in Man Document Reader
    Tbx5 and Nkx2.5 directly bound to the promoter of the gene encoding cardiac ... These data indicated that NKX2.5 is important for regulation of septation during ...
    www.angis.org.au/bin/Databases/BIRX/birx_doc?phtomim+600584
  • Heart Septal Defects, Atrial :: genetics
    Sixteen of the 18 individuals with NKX2.5 mutations in this study had no family ... These findings suggest that NKX2.5 mutations in non-homeodomain regions may be ...
    lib.bioinfo.pl/meid:59223
  • Cardiac homeobox gene NKX2-5 mutations and congenital heart ...
    The coding region of the NKX2-5 locus was amplified by polymerase chain reaction and ... we found a missense change, E21Q, previously reported as pathogenic. ...
    www.ihop-net.org/UniPub/iHOP/gp/9736216.html
  • Cardiac homeobox gene NKX2-5 mutations and congenital heart ...
    OBJECTIVES: We sought to examine the importance of mutations in the cardiac transcription factor gene NKX2-5 in patients with an atrial septal defect (ASD), patent ...
    www.medscape.com/medline/abstract/12798584
  • OMIM: 600584
    Tbx5 and Nkx2.5 directly bound to the promoter of the gene encoding ... Nkx2.5 was expressed in the thyroid primordium up to E11.5; thereafter, Nkx2.5 transcript ...
    www.genome.jp/dbget-bin/www_bget?omim+600584
  • Hypoplastic Left Heart Syndrome :: genetics
    One NKX2-5 mutation-positive child from this family had HLHS, although no mutations were ... Screening for NKX2-5 mutations may be warranted in individuals with ...
    lib.bioinfo.pl/meid:249592

Other in silico analyses
 

  • NBLOSUM100 score = –2
  • GET-Evidence autoscore = 5

Edit history
 

Gene search

"GENE" or "GENE A123C":

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