Detection of nucleotide variant c.650A>G

Question

Good evening, during preconception testing for in vitro fertilization procedure, I was found to be a carrier of the nucleotide variant c.650A>G p.(Glu217Gly) of the CFTR gene (NM_000492.3) in heterozygosity. No copy number variant (CNV) was detected in the CFTR gene (RefSeq NM_000492.3) in the sample under analysis.
The genotype for the -12T variant in intron 8 is T7/T7 and for the -34TG variant is TG12/TG11, and it is a polymorphism without clinical significance. My husband will also undergo a full molecular test, but in the meantime I would like to ask if there will be a problem in a possible pregnancy if he is also found positive for the same or another mutation.
Thank you very much

Answer

The c.650A>G p.(Glu217Gly) variant of the CFTR gene found in you is known and has been described in the literature in various populations. It belongs to the variants of uncertain clinical significance — that is, it is not considered a classic mutation that causes cystic fibrosis, but may in some cases, in combination with another pathological mutation, be associated with mild forms or related clinical syndromes, such as congenital absence of the vas deferens (CBAVD) in men.

Since you are heterozygous, that is, you carry only one "copy" of the variant, you do not have cystic fibrosis but are a carrier.

The crucial thing for pregnancy is whether the husband is also found to be a carrier of a pathogenic variant in the same gene (CFTR). If both parents are carriers (even of different mutations), then there is a 25% chance in each pregnancy that the child will inherit the mutation from both of them, and therefore suffer from cystic fibrosis.

If the husband is not found to be a carrier, then there is no risk of the disease.

If the husband is found to be a carrier of the same mutation or another pathogenic variant, then genetic counseling will be needed to assess the risk and decide on prenatal or preimplantation diagnosis.

Your genotype for the polymorphic variants T7/T7 and TG12/TG11 is not associated with pathology in itself, as you were correctly informed — it is a common polymorphism.

Conclusion:
For now, the important thing is to wait for the husband's results. Only if he is also found to be a carrier, does it need to be discussed further. If he is not, there is no reason to worry.
Best regards,
M. Poulou

25.04.2025