TYR R402Q - GET-Evidence

Curation:
Currentness:

TYR R402Q

(TYR Arg402Gln)


Short summary

This is a frequent pigmentation polymorphism in Europeans that affects function of the Tyrosinase gene. It is associated with blue instead of green eyes and sun sensitivity. For the most part this variant is benign, but many individuals with ocular albinism (which affects only the eyes) carry this variant along with another more severe variant in the same gene.

Variant evidence
Computational 1

Other variants in this gene associated with albinism

Functional 2

Heat sensitivity: 25% enzyme activity at 37C in transfected HeLa cells, and mislocalization at 37C in transfected COS7 cells.

See Tripathi RK et al. 1991 (1820207), Toyofuku K et al. 2001 (11284711).

Case/Control 5

p=0.003 for compound heterozygosity in albinism, high significance findings for blue vs. green eyes and sun sensitivity.

See Sulem P et al. 2008 (18488028), Chiang PW et al. 2009 (19533789).

Familial -
 
Clinical importance
Severity -
Treatability -
Penetrance

Based on data from Hutton et al., we estimate ~0.05% attributable increased risk of ocular albinism. Because this is so low, we evaluate this variant as “benign”.

See Hutton SM et al. 2008 (18326704).

 

Impact

Low clinical importance, benign

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

Inheritance pattern

other

Summary of published research, and additional commentary

 

Allele frequency

  • A @ chr11:89017961: 20.5% (2205/10758) in EVS
  • A @ chr11:88657608: 10.9% (14/128) in GET-Evidence
  • Frequency shown in summary reports: 20.5% (2205/10758)

Publications
 

Tripathi RK, Giebel LB, Strunk KM, Spritz RA. A polymorphism of the human tyrosinase gene is associated with temperature-sensitive enzymatic activity. Gene Expr. 1991 May;1(2):103-10. PubMed PMID: 1820207.

The authors report that this Gln variant has some heat instability, with 25% enzyme activity when expressed in HeLa cells at 37C compared to 31C, while the Arg variant did not show temperature sensitivity.

Fukai K, Holmes SA, Lucchese NJ, Siu VM, Weleber RG, Schnur RE, Spritz RA. Autosomal recessive ocular albinism associated with a functionally significant tyrosinase gene polymorphism. Nat Genet. 1995 Jan;9(1):92-5. PubMed PMID: 7704033.

 

Toyofuku K, Wada I, Spritz RA, Hearing VJ. The molecular basis of oculocutaneous albinism type 1 (OCA1): sorting failure and degradation of mutant tyrosinases results in a lack of pigmentation. Biochem J. 2001 Apr 15;355(Pt 2):259-69. PubMed PMID: 11284711; PubMed Central PMCID: PMC1221735.

These authors report the variant, along with other TYR mutants, mislocalizing to endoplasmic reticulum in COS7 cells at 37C. According to earlier publications, tyrosinase is expressed by transfection in non-pigment cells (like COS7) it is sorted to lysosomes, which is what they observed for the wildtype variant here at 37C. The variant had wildtype localization pattern at 31C.

Hutton SM, Spritz RA. A comprehensive genetic study of autosomal recessive ocular albinism in Caucasian patients. Invest Ophthalmol Vis Sci. 2008 Mar;49(3):868-72. PubMed PMID: 18326704.

In a study of 36 Caucasian patients with autosomal recessive ocular albinism, this variant was seen compound heterozygously with more severe variants in TYR. The authors note that 95% (20 of 21) of cases with mutations in TYR were compound heterozygous with R402Q. Out of 36 cases in total: 402Q/Q: 1, 402Q/R: 26, 402R/R: 9. The authors state that this variant has an allele frequency of ~0.278 based on dbSNP data.

Assuming that frequency is correct, their results have a significance of p = 0.0012. However, ideally the controls against which we would compare would’ve been selected by the authors to be ethnically matched — there may be some variation in allele frequency within different caucasian subpopulations.

If the incidence of ocular albinism is 1 in 1000 (0.1%), we estimate carrying this variant may have an increased attributable risk of 0.056% (total risk of 0.156%).

Gudbjartsson DF, Sulem P, Stacey SN, Goldstein AM, Rafnar T, Sigurgeirsson B, Benediktsdottir KR, Thorisdottir K, Ragnarsson R, Sveinsdottir SG, Magnusson V, Lindblom A, Kostulas K, Botella-Estrada R, Soriano V, Juberías P, Grasa M, Saez B, Andres R, Scherer D, Rudnai P, Gurzau E, Koppova K, Kiemeney LA, Jakobsdottir M, Steinberg S, Helgason A, Gretarsdottir S, Tucker MA, Mayordomo JI, Nagore E, Kumar R, Hansson J, Olafsson JH, Gulcher J, Kong A, Thorsteinsdottir U, Stefansson K. ASIP and TYR pigmentation variants associate with cutaneous melanoma and basal cell carcinoma. Nat Genet. 2008 Jul;40(7):886-91. Epub 2008 May 18. Erratum in: Nat Genet. 2008 Aug;40(8):1029. PubMed PMID: 18488027.

 

Sulem P, Gudbjartsson DF, Stacey SN, Helgason A, Rafnar T, Jakobsdottir M, Steinberg S, Gudjonsson SA, Palsson A, Thorleifsson G, Pálsson S, Sigurgeirsson B, Thorisdottir K, Ragnarsson R, Benediktsdottir KR, Aben KK, Vermeulen SH, Goldstein AM, Tucker MA, Kiemeney LA, Olafsson JH, Gulcher J, Kong A, Thorsteinsdottir U, Stefansson K. Two newly identified genetic determinants of pigmentation in Europeans. Nat Genet. 2008 Jul;40(7):835-7. Epub 2008 May 18. PubMed PMID: 18488028.

GWAS study, confirming and extending similar observations by Sulem et al. 2007 for this variant association with pigmentation.
Blue vs. green eyes, average odds ratio of 1.5, p=4.6e-21.
Blonde vs. brown hair, average odds ratio of 1.33, p=2.7e-5
Skin sensitivity to sun, average odds ratio of 1.25, p=7.1e-13
p < 1.5e-7 was required for genome-wide significance, so the hair pigmentation finding was not significant.

Chiang PW, Spector E, Tsai AC. Oculocutaneous albinism spectrum. Am J Med Genet A. 2009 Jul;149A(7):1590-1. PubMed PMID: 19533789.

After excluding black & asian cases, they examine 23 cases with 1 or 2 mutations in this gene. 10/11 cases with just one mutation are heterozygous for this variant, the other being wildtype. The 12 that already had 2 mutations, 9 were wildtype, 2 were heterozygous, and 1 was homozygous. Grouping hets & homs together, this is case1+: 10, case1-: 1, case2+: 3, case2-: 9. This is p=0.003.

Unclear whether these represent “oculocutaneous albinism” or “ocular albinism”.

Genomes
 

hu025CEA - CGI sample GS01669-DNA_D02 from PGP sample 27316983
het A @ chr11:89017961

 

hu241DEA - CGI sample GS01175-DNA_D05 from PGP sample 1205491
hom A @ chr11:89017961

 

hu2D6140 - CGI sample GS01173-DNA_F06 from PGP sample 64191565
het A @ chr11:89017961

 

 

hu3CAB43 - CGI sample GS01175-DNA_D03 from PGP sample 27486199
het A @ chr11:89017961

 

hu4339C0 - CGI sample GS01175-DNA_H01 from PGP sample 94797469
het A @ chr11:89017961

 

hu44DCFF - CGI sample GS01669-DNA_C07 from PGP sample 74521372
het A @ chr11:89017961

 

hu4CA5B9 - CGI sample GS01669-DNA_B03 from PGP sample 14427241
het A @ chr11:89017961

 

huA0E089 - CGI sample GS01175-DNA_B04 from PGP sample 88590671
het A @ chr11:89017961

 

huBAAC98 - CGI sample GS01173-DNA_F02 from PGP sample 70008981
het A @ chr11:89017961

 

huD37D14 - CGI sample GS01175-DNA_A04 from PGP sample 13272228
hom A @ chr11:89017961

 

huE80E3D - CGI sample GS00253-DNA_D01_200_37
het A @ chr11:89017961

 

huFAF983 - CGI sample GS01175-DNA_F02 from PGP sample 95788191
het A @ chr11:89017961

 

GS06985 - var-GS06985-1100-36-ASM
het A @ chr11:88657609

 

GS07357 - var-GS07357-1100-36-ASM
het A @ chr11:88657609

 

GS10851 - var-GS10851-1100-36-ASM
het A @ chr11:88657609

 

GS12004 - var-GS12004-1100-36-ASM
het A @ chr11:88657609

 

GS19648 - var-GS19648-1100-36-ASM
het A @ chr11:88657609

 

GS19669 - var-GS19669-1100-36-ASM
het A @ chr11:88657609

 

GS19670 - var-GS19670-1100-36-ASM
het A @ chr11:88657609

 

GS19834 - var-GS19834-1100-36-ASM
hom A @ chr11:88657609

 

GS20509 - var-GS20509-1100-36-ASM
het A @ chr11:88657609

 

Other external references
 

    dbSNP
  • rs1126809
    www.ncbi.nlm.nih.gov/projects/SNP/snp_ref.cgi
    PharmGKB
  • [Carcinoma, Basal Cell; Melanoma]
    This variant is associated with the risk of cutaneous melanoma and basal cell carcinoma. It is also stronly associated pigmentation, freckling and skin sensitivity to sun.
    www.ncbi.nlm.nih.gov/pubmed/18488027
    PolyPhen-2
  • Score: 0.997 (probably damaging)

Other in silico analyses
 

  • NBLOSUM100 score = 0
  • GET-Evidence autoscore = 5

Edit history
 

Gene search

"GENE" or "GENE A123C":

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