HNMT T105I - GET-Evidence

Note: This variant has not been sufficiently evaluated by a GET-Evidence editor.

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Curation:
Currentness:

HNMT T105I

(HNMT Thr105Ile)


Short summary

Initial reports implicated this in causing increased susceptibility to asthma, but later reports contradict this. The variant does not appear to be significantly pathogenic, despite computational and experimental evidence that the variant affects enzyme activity.

Variant evidence
Computational 1

Model by Rutherford et al. indicates the residue affects packing, which affects the active site

Functional 2

Kidney cells with this variant and transient expression of the variant in COS-1 cells had lower HNMT activity

Case/Control

If the results of Deindl et al. are combined with Yan et al’s, the association between this variant and asthma is no longer significant.

See Yan L et al. 2000 (10803682), Deindl P et al. 2005 (15693910).

Familial -
 
Clinical importance
Severity 2
Treatability 3
Penetrance -
 

Impact

Insufficiently evaluated pathogenic

(The "insufficiently evaluated" qualifier is assigned automatically based on the above evidence and importance scores.)

Inheritance pattern

other

Summary of published research, and additional commentary

 

Allele frequency

  • T @ chr2:138759649: 7.7% (828/10758) in EVS
  • T @ chr2:138476118: 9.4% (12/128) in GET-Evidence
  • Frequency shown in summary reports: 7.7% (828/10758)

Publications
 

Preuss CV, Wood TC, Szumlanski CL, Raftogianis RB, Otterness DM, Girard B, Scott MC, Weinshilboum RM. Human histamine N-methyltransferase pharmacogenetics: common genetic polymorphisms that alter activity. Mol Pharmacol. 1998 Apr;53(4):708-17. PubMed PMID: 9547362.

Kidney samples with this variant had significantly lower levels of HNMT activity & thermal stability, and COS-1 cells transiently expressing a construct with this variant had significantly lower HMNT activity.

Sasaki Y, Ihara K, Ahmed S, Yamawaki K, Kusuhara K, Nakayama H, Nishima S, Hara T. Lack of association between atopic asthma and polymorphisms of the histamine H1 receptor, histamine H2 receptor, and histamine N-methyltransferase genes. Immunogenetics. 2000 Mar;51(3):238-40. PubMed PMID: 10752634.

 

Yan L, Galinsky RE, Bernstein JA, Liggett SB, Weinshilboum RM. Histamine N-methyltransferase pharmacogenetics: association of a common functional polymorphism with asthma. Pharmacogenetics. 2000 Apr;10(3):261-6. PubMed PMID: 10803682.

Unable to access a copy of this paper online. OMIM reports that 192 cases and 237 were studies, with 54 alleles found in cases and 38 in controls. Counting alleles, this is case+: 54, case-: 330, control+: 38, control-: 436. This is p=0.005 and an OR of 1.88.

Deindl P, Peri-Jerkan S, Deichmann K, Niggemann B, Lau S, Sommerfeld C, Sengler C, Müller S, Wahn U, Nickel R, Heinzmann A; German Multicenter Atopy Study Group. No association of histamine- N-methyltransferase polymorphism with asthma or bronchial hyperresponsiveness in two German pediatric populations. Pediatr Allergy Immunol. 2005 Feb;16(1):40-2. PubMed PMID: 15693910.

In a study of German children, in 261 children with asthma the allele frequency of this variant was 0.13 (similar to Yan et al), while in the 515 non-asthmatic controls the allele frequency was also 0.13. This contradicts Yan et al.‘s finding and is consistent with Sasaki et al’s negative report.

Sharma S, Mann D, Singh TP, Ghosh B. Lack of association of histamine-N-methyltransferase (HNMT) polymorphisms with asthma in the Indian population. J Hum Genet. 2005;50(12):611-7. Epub 2005 Oct 5. PubMed PMID: 16205835.

 

Rutherford K, Parson WW, Daggett V. The histamine N-methyltransferase T105I polymorphism affects active site structure and dynamics. Biochemistry. 2008 Jan 22;47(3):893-901. Epub 2007 Dec 23. PubMed PMID: 18154359.

 

Genomes
 

hu034DB1 - CGI sample GS00253-DNA_A02_200_37
het T @ chr2:138759649

 

 

hu2D6140 - CGI sample GS01173-DNA_F06 from PGP sample 64191565
het T @ chr2:138759649

 

hu44DCFF - CGI sample GS01669-DNA_C07 from PGP sample 74521372
het T @ chr2:138759649

 

hu8229AE - CGI sample GS01173-DNA_A07 from PGP sample 96240009
het T @ chr2:138759649

 

huBAAC98 - CGI sample GS01173-DNA_F02 from PGP sample 70008981
het T @ chr2:138759649

 

GS06994 - var-GS06994-1100-36-ASM
het T @ chr2:138476119

 

GS12004 - var-GS12004-1100-36-ASM
het T @ chr2:138476119

 

GS18537 - var-GS18537-1100-36-ASM
het T @ chr2:138476119

 

GS19649 - var-GS19649-1100-36-ASM
het T @ chr2:138476119

 

GS19704 - var-GS19704-1100-36-ASM
het T @ chr2:138476119

 

NA12878

 

Other external references
 

    dbSNP
  • rs11558538
    www.ncbi.nlm.nih.gov/projects/SNP/snp_ref.cgi
    PolyPhen-2
  • Score: 0.821 (possibly damaging)

Other in silico analyses
 

  • NBLOSUM100 score = 3
  • GET-Evidence autoscore = 2

Edit history
 

Gene search

"GENE" or "GENE A123C":

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