LOXL1 R141L - GET-Evidence



(LOXL1 Arg141Leu)

Short summary

Associated with exfoliative glaucoma & syndrome (XFG & XFS) in various populations, but with contradicting results (protective in Caucasians, pathogenic in Japanese). Based on this it seems the variation itself — although it affects protein structure — is not itself causing disease. Instead it is likely associated with other nearby causal variants. As such, it is evaluated as benign by GET-Evidence (which focuses on reporting causal variants). See detailed variant report for disease risk associations.

Variant evidence
Computational -1

PPH2 predicts probably damaging


No functional data


Contradicting results with strong associations, see below.

See Thorleifsson G et al. 2007 (17690259), Ozaki M et al. 2008 (18450598).

Familial -
Clinical importance
Severity -
Treatability -
Penetrance -


Low clinical importance, Uncertain benign

(The "low clinical importance, uncertain" qualifier is assigned automatically based on the above evidence and importance scores.)

Inheritance pattern


Summary of published research, and additional commentary


Allele frequency

  • T @ chr15:74219546: 25.6% (2646/10340) in EVS
  • Frequency shown in summary reports: 25.6% (2646/10340)


Thorleifsson G, Magnusson KP, Sulem P, Walters GB, Gudbjartsson DF, Stefansson H, Jonsson T, Jonasdottir A, Jonasdottir A, Stefansdottir G, Masson G, Hardarson GA, Petursson H, Arnarsson A, Motallebipour M, Wallerman O, Wadelius C, Gulcher JR, Thorsteinsdottir U, Kong A, Jonasson F, Stefansson K. Common sequence variants in the LOXL1 gene confer susceptibility to exfoliation glaucoma. Science. 2007 Sep 7;317(5843):1397-400. Epub 2007 Aug 9. PubMed PMID: 17690259.

This variant position (rs1048661) was found to be strongly associated with exfoliation glaucoma (XFG) in icelandic and swedish individuals. The variant conferring more risk was the “G” allele — which is the reference variant (141R) — and so 141L would be interpreted as having a protective effect. In their study, they found the G allele had a frequency of 0.65 in controls and 0.83 cases of XFG.

They also report this genotype is associated with significant difference is gene expression. However, the method did not independently introduce this variant to constructs to measure its effect on expression alone; rather, they looked at expression data from individuals who happen to carry the genotype. This means the expression differences could be caused by other nearby linked genetic variants, rather than rs1048661 itself.

Because they report no significant deviation from Hardy-Weinberg equilibrium in cases and controls, their allele frequencies imply genotype frequencies in cases of GG=.69 / GT=.28 / TT=0.3 and in controls of GG=0.42 / GT=0.45 / TT = 0.12. Controls were not chosen as specifically excluding the disease.

To estimate how carrying this variant affects lifetime risk for XFG in these populations, we would like to compare average risk vs. risk dependent on genotype. Assuming a lifetime risk for XFG of 15%, we would estimate the non-XFG group to have genotype frequencies of GG=0.38 / GT=0.48 / TT=0.14. (i.e. for GG, 0.42 = 0.15 * 0.69 + 0.85 * 0.38, etc.) Using this, GG’s lifetime risk for disease is 0.24 = (.69*.15 / (.69 * .15 + .38 * .85)), GT’s risk = 0.09, TT’s risk = .04. From this perspective, carrying 141L homozygously is associated with being protective having 11% decreased attributable risk and GT protective with 6% decreased attributable risk (while homozygosity for the reference GG genotype is pathogenic with 9% increased attributable risk).

Ozaki M, Lee KY, Vithana EN, Yong VH, Thalamuthu A, Mizoguchi T, Venkatraman A, Aung T. Association of LOXL1 gene polymorphisms with pseudoexfoliation in the Japanese. Invest Ophthalmol Vis Sci. 2008 Sep;49(9):3976-80. Epub 2008 Apr 30. PubMed PMID: 18450598.

This study of the Japanese population found an inverted association of this variant with XFG — the T variant (141L) was the “risk allele”, found to be much more common in XFG/XFS cases than the G variant (141R). In controls, T had an allele frequency of 0.50, while in XFG/XFS cases the frequency was 0.95.

Assuming Hardy-Weinberg equilibrium, this implies controls have genotype frequencies of GG=.25, GT=.50, TT/.25, and cases GG=.003,GT=.095,TT=0.90.

The authors note prevalence of XFS in Japanese reported to be around 1-3%. Assuming a prevalence of 2%, we would guess the TT genotype to have ~7% risk of disease (5% increased attributable risk) (.07 = (.02 * .9) / (.02 * .9 + .98 * .25) ), the GT to have around average risk, and GG to have nearly zero (2% decreased attributable risk).

As noted by Chen et al., the strongly contrasting association result here implies that this variant is not itself causal, but that these genotypes are associated with some other variant in LOXL1 causing the disease (and the associations happen to be inverted in the different ethnicities).

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PubMed PMID: 20142848

These authors note numerous studies from Caucasian vs. Japanese ethnicities have a strong but consistently opposite results for the rs1048661 variant’s association with exfoliation glaucoma (see Figure 4). Based on this, they conclude the variant is not itself causal, but instead associated with other pathogenic variants within the gene. (And the association happens to be different for the two populations.)


hu011C57 - CGI sample GS01669-DNA_B05 from PGP sample 86486261
het T @ chr15:74219546


hu025CEA - CGI sample GS01669-DNA_D02 from PGP sample 27316983
het T @ chr15:74219546


hu0E64A1 - CGI sample GS01173-DNA_B02 from PGP sample 94378523
het T @ chr15:74219546



hu241DEA - CGI sample GS01175-DNA_D05 from PGP sample 1205491
hom T @ chr15:74219546


hu2D6140 - CGI sample GS01173-DNA_F06 from PGP sample 64191565
hom T @ chr15:74219546


hu342A08 - CGI sample GS01175-DNA_B05 from PGP sample 83494370
het T @ chr15:74219546


hu38168C - CGI sample GS01173-DNA_H06 from PGP sample 91708424
het T @ chr15:74219546


hu4040B8 - CGI sample GS01175-DNA_D01 from PGP sample 31286272
het T @ chr15:74219546


hu4339C0 - CGI sample GS01175-DNA_H01 from PGP sample 94797469
het T @ chr15:74219546


hu44DCFF - CGI sample GS01669-DNA_C07 from PGP sample 74521372
het T @ chr15:74219546


hu92FD55 - CGI sample GS01669-DNA_A04 from PGP sample 08188426
hom T @ chr15:74219546


huA0E089 - CGI sample GS01175-DNA_B04 from PGP sample 88590671
het T @ chr15:74219546


huAE4A11 - CGI sample GS01669-DNA_F02 from PGP sample 40767107
het T @ chr15:74219546


huB1FD55 - CGI sample GS01173-DNA_B07 from PGP sample 61499538
hom T @ chr15:74219546


huBAAC98 - CGI sample GS01173-DNA_F02 from PGP sample 70008981
het T @ chr15:74219546


huCA017E - CGI sample GS01175-DNA_B01 from PGP sample 86206034
het T @ chr15:74219546






Other external references

  • rs1048661
  • [Exfoliation Syndrome]
    In a case-control GWAS of Icelandic and Swedish patients, the G allele of rs1048661 was significantly associated with risk of Exfoliation Syndrome Glaucoma.
  • Score: 0.998 (probably damaging)

Other in silico analyses

  • NBLOSUM100 score = 6
  • GET-Evidence autoscore = 3

Edit history

Gene search

"GENE" or "GENE A123C":

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