TCIRG1 R56W - GET-Evidence



(TCIRG1 Arg56Trp)

Short summary

Probably benign. One publication implicates the variant in causing osteopetrosis, but this is contradicted by the relatively high allele frequency for the variant in Caucasians (5%, 1 in 400 homozygous) while that disease is extremely rare (1 in 250,000).

Variant evidence
Computational -1

BLOSUM100 predict Arg to Trp is disruptive, Polyphen 2 predicts damaging effect

Functional -
Case/Control 5

Allele frequency strongly contradicts this variant causing osteopetrosis, which is extremely rare.

See Carn G et al. 2002 (12161516), unpublished research (below).

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

The incidence of osteopetrosis, as implied by Schinke et al., is extremely rare — 1 in 250,000 according to this orphanet estimate:

With an allele frequency of 5% in whites, about 1 in 400 individuals would be homozygous for this variant — this is several orders of magnitude higher than the incidence of the disease. In addition, OMIM does not mention this variant — if it played a causal role in the disease it would almost certainly have been observed and well-reported on by now.

To establish significance for the observations of this variant in samples from the general population, we test it against a hypothetical variant with moderate penetrance (5%) for causing osteopetrosis in a recessive manner and responsible for 50% of cases (1 in 25,000 homozygous, 1 in 500,000 affected). Such a hypothetical variant would be expected to have an allele frequency 0.63%. Using the HapMap data: the chances of seeing this 30 times or more in a sample of 1,140 alleles is p=1.45 * 10^-10.

Allele frequency

  • T @ chr11:67809268: 4.4% (475/10752) in EVS
  • T @ chr11:67565843: 1.6% (2/128) in GET-Evidence
  • Frequency shown in summary reports: 4.4% (475/10752)


Carn G, Koller DL, Peacock M, Hui SL, Evans WE, Conneally PM, Johnston CC Jr, Foroud T, Econs MJ. Sibling pair linkage and association studies between peak bone mineral density and the gene locus for the osteoclast-specific subunit (OC116) of the vacuolar proton pump on chromosome 11p12-13. J Clin Endocrinol Metab. 2002 Aug;87(8):3819-24. PubMed PMID: 12161516.

These authors describe the variant (also called C226T) as a polymorphism with an allele frequency of ~5% in Caucasians and not found in their African American controls.

Schinke T, Schilling AF, Baranowsky A, Seitz S, Marshall RP, Linn T, Blaeker M, Huebner AK, Schulz A, Simon R, Gebauer M, Priemel M, Kornak U, Perkovic S, Barvencik F, Beil FT, Del Fattore A, Frattini A, Streichert T, Pueschel K, Villa A, Debatin KM, Rueger JM, Teti A, Zustin J, Sauter G, Amling M. Impaired gastric acidification negatively affects calcium homeostasis and bone mass. Nat Med. 2009 Jun;15(6):674-81. PubMed PMID: 19448635.

These authors describe this variant (R56W) as homozygous in a patient sample described as “an individual with TCIRG1-dependent osteopetrosis” (Figure 3e). The methods describe this sample: “A case of TCIRG1-dependent osteopetrosis in an 18-month-old child was confirmed by automated sequencing of all TCIRG1-encoding exons and also by conventional X-ray analysis demonstrating growth-plate widening.”


hu43860C - CGI sample GS00253-DNA_A01_200_37
het T @ chr11:67809268



hu72A81D - CGI sample GS01173-DNA_C02 from PGP sample 10366372
het T @ chr11:67809268


huFFAD87 - CGI sample GS01669-DNA_H05 from PGP sample 10971581
het T @ chr11:67809268


Other external references

  • rs36027301
  • Score: 0.995 (probably damaging)

Other in silico analyses

  • NBLOSUM100 score = 7
  • GET-Evidence autoscore = 4

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Gene search

"GENE" or "GENE A123C":

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