ARMS2 R38X - GET-Evidence

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(ARMS2 Arg38Stop)

Short summary


Variant evidence
Computational -
Functional -
Case/Control -
Familial -
Clinical importance
Severity -
Treatability -
Penetrance -


Insufficiently evaluated not reviewed

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

Inheritance pattern


Summary of published research, and additional commentary


Allele frequency

  • T @ chr10:124214355: 12.1% (1231/10176) in EVS
  • T @ chr10:124204344: 13.3% (17/128) in GET-Evidence
  • Frequency shown in summary reports: 12.1% (1231/10176)


Yang Z, Tong Z, Chen Y, Zeng J, Lu F, Sun X, Zhao C, Wang K, Davey L, Chen H, London N, Muramatsu D, Salasar F, Carmona R, Kasuga D, Wang X, Bedell M, Dixie M, Zhao P, Yang R, Gibbs D, Liu X, Li Y, Li C, Li Y, Campochiaro B, Constantine R, Zack DJ, Campochiaro P, Fu Y, Li DY, Katsanis N, Zhang K. Genetic and functional dissection of HTRA1 and LOC387715 in age-related macular degeneration. PLoS Genet. 2010 Feb 5;6(2):e1000836. doi: 10.1371/journal.pgen.1000836. PubMed PMID: 20140183; PubMed Central PMCID: PMC2816682.

A common haplotype on 10q26 influences the risk of age-related macular degeneration (AMD) and encompasses two genes, LOC387715 and HTRA1. Recent data have suggested that loss of LOC387715, mediated by an insertion/deletion (in/del) that destabilizes its message, is causally related with the disorder. Here we show that loss of LOC387715 is insufficient to explain AMD susceptibility, since a nonsense mutation (R38X) in this gene that leads to loss of its message resides in a protective haplotype. At the same time, the common disease haplotype tagged by the in/del and rs11200638 has an effect on the transcriptional upregulation of the adjacent gene, HTRA1. These data implicate increased HTRA1 expression in the pathogenesis of AMD and highlight the importance of exploring multiple functional consequences of alleles in haplotypes that confer susceptibility to complex traits.

Friedrich U, Myers CA, Fritsche LG, Milenkovich A, Wolf A, Corbo JC, Weber BH. Risk- and non-risk-associated variants at the 10q26 AMD locus influence ARMS2 mRNA expression but exclude pathogenic effects due to protein deficiency. Hum Mol Genet. 2011 Apr 1;20(7):1387-99. doi: 10.1093/hmg/ddr020. Epub 2011 Jan 20. PubMed PMID: 21252205; PubMed Central PMCID: PMC3049360.

Fifteen variants in 10q26 are in strong linkage disequilibrium and are associated with an increased risk for age-related macular degeneration (AMD), a frequent cause of blindness in developed countries. These variants tag a single-risk haplotype encompassing the genes ARMS2 (age-related maculopathy susceptibility 2) and part of HTRA1 (HtrA serine peptidase 1). To define the true AMD susceptibility gene in 10q26, several studies have focused on the influence of risk alleles on the expression of ARMS2 and/or HTRA1, but the results have been inconsistent. By heterologous expression of genomic ARMS2 variants, we now show that ARMS2 mRNA levels transcribed from the risk haplotype are significantly reduced compared with non-risk mRNA isoforms. Analyzing variant ARMS2 constructs, this effect could specifically be assigned to the known insertion/deletion polymorphism (c.(*)372_815del443ins54) in the 3’-untranslated region of ARMS2. Reporter gene assays with HTRA1 promoter sequences demonstrated the presence of a Müller glia-specific cis-regulatory region further upstream of the transcription start site. However, AMD risk alleles had little or no effect on HTRA1 promoter activity in the retina. Analysis of a large series of human post-mortem retina/retinal pigment epithelial samples heterozygous for the risk haplotype confirmed the in vitro/ex vivo results and demonstrated that the risk haplotype affects ARMS2 but not HTRA1 mRNA expression. Furthermore, we provide in vivo evidence that a common non-risk-associated non-synonymous variant (rs2736911) also leads to decreased ARMS2 transcript levels. Consequently, our data suggest that pathogenic effects due to ARMS2 protein deficiency are unlikely to account for AMD pathology.

Teper SJ, Nowińska A, Wylęgała E. A69S and R38X ARMS2 and Y402H CFH gene polymorphisms as risk factors for neovascular age-related macular degeneration in Poland - a brief report. Med Sci Monit. 2012 Feb;18(2):PR1-3. PubMed PMID: 22293892; PubMed Central PMCID: PMC3560583.

Homozygous Y402H and A69S conferred a significance risk of wet ARMD in Poland: Y402H odds ratio (OR) was 5.57 (95% confidence interval: 1.58–19.6), p=0.002; and A69S OR was 7.72 (95% confidence interval: 1.73–34.36), p=0.001. R38X is probably more common in healthy subjects: OR was 0.45 (95% confidence interval: 0.19–1.05), p=0.053.

The etiologic role in ARMD of A69S ARMS2 and Y402H CFH gene variants were confirmed in a Polish population for the first time. R38X variant of ARMS2 seems to be protective from wet ARMD.

Wang G, Scott WK, Agarwal A, Haines JL, Pericak-Vance MA. Coding Variants in ARMS2 and the Risk of Age-Related Macular Degeneration. JAMA Ophthalmol. 2013 Apr 9:1-2. doi: 10.1001/jamaophthalmol.2013.589. [Epub ahead of print] PubMed PMID: 23572227.

Genetic variation at the chromosome 10q26 locus is strongly associated with the risk of age-related macular degeneration (AMD). Recently, the common coding variant rs2736911 (R38X) in the age-related maculopathy susceptibility 2 gene (ARMS2; GenBank NG_011725) was inversely associated with AMD. The R38X variant introduces a premature stop codon that likely leads to a truncated ARMS2 protein at a lower expression level due to nonsense-mediated decay. It remains unclear how the missense change A69S increases the risk of AMD, while the truncated R38X is protective. To understand the association of R38X with AMD, we examined 3 ARMS2 common coding variants, R38X, A69S, and rs10490923 (R3H), as well as the HTRA1 promoter variant rs11200638 in a large case-control data set.


hu04FD18 - CGI sample GS00253-DNA_F01_200_37
het T @ chr10:124214355


hu0E64A1 - CGI sample GS01173-DNA_B02 from PGP sample 94378523
hom T @ chr10:124214355


hu2D6140 - CGI sample GS01173-DNA_F06 from PGP sample 64191565
het T @ chr10:124214355




hu92FD55 - CGI sample GS01669-DNA_A04 from PGP sample 08188426
het T @ chr10:124214355


hu9385BA - CGI sample GS00253-DNA_E01_200_37
het T @ chr10:124214355


huAE6220 - CGI sample GS00253-DNA_H01_200_37
het T @ chr10:124214355


huBAAC98 - CGI sample GS01173-DNA_F02 from PGP sample 70008981
het T @ chr10:124214355


huBEDA0B - CGI sample GS00253-DNA_C01_200_37
hom T @ chr10:124214355


huC30901 - CGI sample GS00253-DNA_B01_200_37
het T @ chr10:124214355


huCA017E - CGI sample GS01175-DNA_B01 from PGP sample 86206034
het T @ chr10:124214355


GS10851 - var-GS10851-1100-36-ASM
het T @ chr10:124204345


GS12004 - var-GS12004-1100-36-ASM
het T @ chr10:124204345


GS18505 - var-GS18505-1100-36-ASM
het T @ chr10:124204345


GS18940 - var-GS18940-1100-36-ASM
het T @ chr10:124204345


GS18947 - var-GS18947-1100-36-ASM
het T @ chr10:124204345


GS19017 - var-GS19017-1100-36-ASM
het T @ chr10:124204345


GS19026 - var-GS19026-1100-36-ASM
het T @ chr10:124204345


GS19670 - var-GS19670-1100-36-ASM
het T @ chr10:124204345


Other external references

  • rs2736911
    Web search results (4 hits -- see all)
  • Multilocus analysis of age-related macular degeneration
    The chromosome 10q26 locus containing the ARMS2 and HTRA1 genes is highly associated with ... a non-sense allele in ARMS2 (R38X) does not appear to confer ...
  • PLoS Genetics: Genetic and Functional Dissection of HTRA1 and ...
    A locus for AMD, ARMS2 on 10q26, illustrates this challenge. ARMS2 is one of several ... However, the introduction of the R38X mutation, which is also predicted to give rise to ...
  • НÐμсÑ"абР̧Ð"ьная ARMS2 мРНК
    Внтури интервала ARMS2-HTRA1 Fritsche et al. определили генотип 28 ... R38X, которая может потенциально оказывать то же самое влияние на уровень белка ARMS2. ...
  • Untersuchungen zu den genetischen Ursachen der ...
    Hierzu wurde die 107 kb-große PLEKHA1-ARMS2-HTRA1-Region durch 28 häufige SNPs ... (Heterozygotie für ARMS2-Ser69 und Homozygotie für CFH-His402 oder vice versa) ...

Other in silico analyses

  • NBLOSUM100 score = 10
  • GET-Evidence autoscore = 3

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Gene search

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