Australian Mutation Statistics

Updated 20/5/15

These mutation statistics are from the 2012 Australian data registry report. I have grouped the mutations based on known classes and the graph below.

Class 3 (Gating) Total = 7.6%
G551D    200   7.4%
S549N     5      0.2%

Kalydeco is approved for G551D and other gating mutations (G178R, S549N, S549R, G551S, G1244E, S1251N, S1255P and G1349D) in Australia. Some of these mutations are very rare and could be included under ‘other.’

Class 4 & 5 (Residual Function) Total = 5.5%
R117H                91  3.4%

D1152H              13  0.5%
P67L                  12   0.4%
3849+10kbC>T   8   0.3%
A455E                 7   0.3%
2789+5G>A        5   0.2%
R117C                 4   0.1%
R347H                 4   0.1%
S1235R               4   0.1%
S945L                  2   0.1%

These mutations have a small amount of baseline chloride transport (see graph below).  R117H is approved in the US and the approval process is underway in Europe and Australia. Other residual function mutations are currently in trials with Kalydeco. Approx 15% of the Aus population are pancreatic sufficient, which is associated with residual function, so the total percentage may be higher (possibly including more from the other/unknown categories).

Class 4 (Conductance)
R334W      7    0.3%
R347P       6    0.2%

These are considered to be class 4 conductance mutations, but they have minimal baseline function and according to the graph below, do not respond to Kalydeco.

Class 2 (F508del – Processing) Total = 85.3%
Homozygous (two copies)    1,406   51.8%
Heterozygous (one copy)      910     33.5%

F508del homozygous patients have finished trials with Orkambi (Lumacaftor & Kalydeco). The approval process is underway in the US, Europe and Australia.

Some F508del heterozygotes have a second mutation that may be helped by Kalydeco or a corrector. Triple therapy (Kalydeco and two correctors) may further help F508del heterozygotes who have a second mutation that does not respond to Kalydeco.

Other Class 2 (Processing) Total = 3.0%
N1303K    46   1.7%
I507del      9    0.3%
R560T       9    0.3%
G85E         7    0.3%
V520F       7    0.3%
R1066C     3    0.1%

These mutations have minimal baseline chloride transport and do not respond to Kalydeco alone (see graph below). Similar to F508del, they may respond to correctors such as Lumacaftor.

Class 1 (Nonsense) Total = 5.2%
G542X      78    2.9%

R553X      20    0.7%
W1282X   22    0.8%
R1162X     8     0.3%
E60X         8     0.3%
Q493X       6     0.2%

Ataluren is in trials with nonsense mutations.

Class 1 (Splicing) Total = 2.6%
1717-1G>A   34   1.3%

621+1G>T    25   0.9%
1898+1G>A   7    0.3%
1525-1G>A    4    0.1%

Class 1 (Frameshift) Total = 1.4%
3659delC       7    0.3%

394delT         5    0.2%
2789+2insA   7    0.3%
1154insTC     3    0.1%
2183AA>G    3    0.1%
1078delT       6    0.2%
2184delA       5    0.2%

Minimal correct CFTR is made with class 1 splicing and frameshift mutations. These mutations are difficult to help based on the current medications in trials, however approaches that change the DNA or RNA may help, as well as altering ENaC.

Other          501    18.5%
Unknown    407    15.0%
Missing       54      2.0%   (People with two missing genes not included)

Total = 2,715     (There were 3156 people in the report, so approx 400 were not included)

Kalydeco with class 2, 3, 4 and 5 mutations

This graph is from a Vertex Investor Conference held Oct 2012.

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