Specific Mutation Info

I have been asked about several mutations so I decided to start this page. If your mutation is not mentioned feel free to ask below.

My sources: google, google scholar, cftr2, cftr1. If you are searching for info about your mutation cftr1 and cftr2 are the best places to start. Journal articles can be found through google scholar.

Common questions:

What is a missense mutation? Missense means one amino acid is changed for another one, it does not refer to one class. Missense mutations have a letter, than a number, then a letter. No arrows, X, del or ins. With G551D, the G amino acid has been replaced with a D. Missense mutations are generally class 2, 3, 4, 5 or 6.

What is a nonsense mutation? A nonsense mutation involves a premature stop codon occuring before the normal end of a protein. This generally means a shorter protein is formed, that is destroyed and does not reach the cell surface. These mutations have an X, eg G542X and W1282X. These are mostly class 1.

What is a splicing mutation? Splicing mutations can be class 1 or class 5. Class 1 splicing mutations have very minimal correct splicing, which means minimal correct protein reaching the cell surface. Class 5 splicing have occasional correct splicing, which means some correct protein reaching the cell surface. Splicing mutations generally have an >  eg 621+1G>T. There is more information about splicing here.

The mutations below are rare. Many mutations are mentioned in this link, have a read if you are looking for a mutation: mutations-involved-with-the-kalydeco-vx809-vx661-n6022-ataluren-trials/

NB: These are my thoughts on specific mutations based on current research (which is evolving quickly), I am not a geneticist
but have studied a biomedical science degree majoring in genetics.

394delTT (CFTR1 Info, CFTR2 Info) Class 1 Frameshift

This mutation has a deletion of two T bases. This deletion results in a frameshift which means almost everything after this point will be incorrect and also that a premature stop codon is formed just after the mutation. Correctors and potentiators are unlikely to help, it is more likely that gene therapy and other research (eg ENaC) could help. This mutation is also known as c.262_263delTT.

405+10255delC (CFTR1 Info) Likely Splicing

This mutation has a deletion of the C base in intron 3. This deletion is not in the DNA that becomes part of the protein, however this deletion may affect splicing of the correct protein. There is more information about splicing here: https://sixtyfiverosesblog.wordpress.com/cf-mutation-classes/. I could not find information about this mutation on CFTR2 or on google scholar, so I am not sure if it is more likely to be class 1 or 5. If there is some correct splicing Kalydeco may help, if there is minimal correct splicing it is more likely that gene therapy or other approaches may help. This mutation is also known as c.273+10255delC.

4209TGTT->AA (CFTR1 Info, CFTR2 Info) Likely Class 1 Frameshift

This mutation involves TGTT being replaced with AA. This replacement results in a frameshift which means almost everything after that point is incorrect. 1360 amino acids are produced correctly, but the CFTR protein is normally 1480 amino acids long. I am not sure if 1360 is enough of the protein to be functional.

There is a class 6 mutation (residual function) where the CFTR reaches the surface and works, but is unstable as it only has 1400 amino acids. There is a slim chance that 1360 amino acids may be enough to also reach the surface and work. However, it is more likely that this does not reach the surface and/or function normally (based on clinical characteristics in CFTR2), which would mean it would be class 1. If this is the case correctors and potentiators are unlikely to help, it is more likely that gene therapy and other research (eg ENaC) could help. This mutation is also known as c.4077_4080delTGTTinsAA.

711+1G>T (CFTR1 Info, CFTR2 Info) Class 1 Splicing

711+1G>T is thought to be a class 1 splicing mutation with minimal correct protein at the cell surface (First Article & Second Article). Correctors and potentiators are unlikely to help, it is more likely that gene therapy and other research could help. This mutation is also known as c.579+1G>T.

I507del (CFTR1 Info, CFTR2 Info) Class 2 Processing

I507del involves a deletion of the I amino acid at position 507. This is a class 2 processing mutation. Laboratory tests have shown that VX809 may not help I507del significantly: https://sixtyfiverosesblog.wordpress.com/2013/03/26/can-vx809-help-other-processing-mutations-besides-f508del/ Based only on that information it is hard to say whether someone with I507del could improve with VX809. It is possible that other correctors, potentially from different companies, may help I507del to a greater extent.

R117C (CFTR1 Info, CFTR2 Info) Residual Function
This is a missense mutation, where the R amino acid has been replaced by the C amino acid. It is a residual function mutation, potentially involving gating and/or conductance (Article 1). It has a low level of baseline CFTR function (approx 5%), as seen in the second graph here, and when Kalydeco is added the function improves to approx 25%. Future research with new potentiators may increase this percentage further. It is similar to R117H as they are at the same position, however the amino acid change is different. In comparison to R117H, R117C has a lower level of baseline function and a smaller improvement with Kalydeco (see link to graph above)
.

R560T (CFTR1, CFTR2) Likely Class 2 Processing

This is a missense mutation, where the R amino acid has been replaced by the T amino acid. It has been previously thought this amino acid change may lead to a splicing defect, but the latest research suggests R560T is a class 2 processing mutation (Article 1 & Article 2).

The Vertex graphs show that R560T is not helped by Kalydeco, and a recent study found that VX809 did not appear to help R560T: https://sixtyfiverosesblog.wordpress.com/2013/03/26/can-vx809-help-other-processing-mutations-besides-f508del/It is possible that other correctors, potentially from different companies, may help R560T to a greater extent.

Still under construction: will post about these:

1359DLC
c.3808 del G frameshift
G85e
3659delC
2183AA>G
2751
Y563N

Join the conversation! 7 Comments

  1. Someone from another forum sent me your way. I have a 14 year old daughter who has had severe lung problems and stomach issues since birth. They started suspecting CF when she was 11 months old. Been seeing a doctor at a CF clinic since then. We have really had no answers until about a year ago. She was not gaining weight and was 80lbsand 5’5″. They started enzymes and magically she began to grow and gain weight. They told me 6 months ago that she has CRMS. 2 months ago she was hospitalized with a mucus plug and partially collapsed lung. They changed her diagnosis to CF. She has a borderline sweat chloride and her genome is M470V and r75q with a 7t/5t variant. This is all very confusing and I am not finding very much on the net about it. Wondering if you have found anything in your own research.

    Reply
    • Hi Cassandra, Sorry I have taken so long to reply. Do you know if M470V is on one chromosome and R75Q on the other one? This is the likely scenario. One of these chromosomes also has the 5T and the other 7T.

      M470V is thought to be a variation that alone does not cause CF: http://www.cftr2.org/mutation.php?view=general&mutation_id=66. R75Q is also thought to be a variation that does not cause CF: http://www.cftr2.org/mutation.php?view=general&mutation_id=92.

      However one of these variations also has 5T on the same chromosome and the other has 7T. 9T is normal, this allows normal amounts of functional protein to be made. 5T and 7T mean that less functional protein will be made compared to normal. There is an explanation about this here: http://www.cfmedicine.com/htmldocs/CFText/genetics.htm

      It is possible the combination of the two variations with the lower amounts of functional protein may explain her presentation. The information above and the fact she has a borderline sweat test means it is possible she has residual function (a low level of functional protein at the surface). This means correctors such as Kalydeco may help.

      Reply
  2. Curious what you’ll find about 405+10255delC

    Reply
    • Hi Christie, I have added some info above about 405+10255delC. There is not much information available so it is hard to say if it is more likely to be class 1 splicing or class 5 splicing. However if someone with this mutation has a lower sweat test, pancreatic sufficiency or milder lung disease than expected, its possible it is class 5 (and vice versa). Gen

      Reply
  3. how about deltaF508 and 1717 g to a?

    Reply
  4. Hi,

    I’m wondering if you have had a chance to investigate the 2183AA>G frameshift mutation and if there are any correctors in the making of or are being tested for this type of mutation? What other companies should we be looking out for besides Vertex? I ask because my niece’s other mutation is R560T and you did a great job of explaining how it did not respond to VX-809 and would not be helped by VX-770.

    Thanks for any help you can provide. Fran

    Reply
  5. Hi
    My mutations are F508/4005+2t>G, and I wonder if you know anything about the 4005+2t>G
    I can’t find any information about it.

    Reply

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