ABCMdb

PMID: 24014130

Langfelder-Schwind E, Karczeski B, Strecker MN, Redman J, Sugarman EA, Zaleski C, Brown T, Keiles S, Powers A, Ghate S, Darrah R
Molecular testing for cystic fibrosis carrier status practice guidelines: recommendations of the National Society of Genetic Counselors.
J Genet Couns. 2014 Feb;23(1):5-15. doi: 10.1007/s10897-013-9636-9. Epub 2013 Sep 7., [PubMed]

Sentences

No. Mutations Sentence Comment

56 ABCC7 p.Gly551Asp The compound Ivacaftor has been FDA approved as a treatment for CF patients carrying at least one copy of the G551D CFTR mutation and is under investigation as a treatment for patients with other CFTR mutations (see www.cff.org; www.clinicaltrials.gov). Login to comment 95 ABCC7 p.Ile148Thr Evolution of Test Panels and Their Interpretation: The Example of I148T/3199del6 Large-scale population carrier screening is providing new information regarding the frequency of alleles in healthy and patient populations. Login to comment 96 ABCC7 p.Ile148Thr A key example is the I148T/3199del6 mutation. Login to comment 97 ABCC7 p.Ile148Thr Initially, I148T was included on the ACOG/ACMG standard mutation panel (ACOG and ACMG 2001). Login to comment 98 ABCC7 p.Ile148Thr However, it was later learned that I148T only behaved as a deleterious mutation when in cis with 3199del6. Login to comment 99 ABCC7 p.Ile148Thr Individuals with a known deleterious mutation in trans to an I148T mutation in the absence of a cis 3199del6 were asymptomatic (Monaghan et al. 2004). Login to comment 100 ABCC7 p.Ile148Thr As a result, I148T was removed from the ACMG standard mutation panel (Rohlfs et al. 2002; Buller et al. 2004). Login to comment 136 ABCC7 p.Arg117His ABCC7 p.Arg117His Table 4 Online information for patients and providers Genetics Home Reference ghr.nlm.nih.gov/condition/ cystic-fibrosis Cystic-L - Cystic Fibrosis Information and Support www.cystic-l.org CysticFibrosis.com www.cysticfibrosis.com CFvoice (by Novartis) www.cfvoice.com Cystic Fibrosis Foundation www.cff.org Canadian Cystic Fibrosis Foundation www.cysticfibrosis.ca European Cystic Fibrosis Society www.ecfs.eu Cystic Fibrosis Trust www.cftrust.org.uk CFTR2 www.cftr2.org For providers only GeneTests/GeneReviews www.genetests.org Cystic Fibrosis Mutation Database www.genet.sickkids.on.ca R117H/PolyT The disease-causing potential of the R117H mutation is influenced by the cis status of a haplotype that includes a polymorphic tract of thymidines (5T, 7T and 9T) and a variable length TG repeat tract (see below) in intron 8 of CFTR near the splice site for exon 9 (Kiesewetter et al. 1993). Login to comment 140 ABCC7 p.Arg117His ABCC7 p.Arg117His Individuals with a disease-causing CFTR mutation in trans to R117H/5T typically have PS cystic fibrosis, whereas individuals with a CFTR mutation in trans to R117H/7T are more likely to be asymptomatic (possibly CRMS if an elevated IRT was detected on the CF NBS) or have a phenotype consistent with a CFTR-related disorder (Massie et al. 2001; Kiesewetter et al. 1993). Login to comment 141 ABCC7 p.Arg117His R117H/9T is highly unlikely to act as a disease-causing mutation (CFTR2, 2013). Login to comment 142 ABCC7 p.Arg117His Infants with a positive CF NBS diagnosed with CRMS are commonly found to have a genotype consisting of one disease causing mutation and either R117H-7T or 5T in trans to that mutation (Borowitz et al. 2009). Login to comment 143 ABCC7 p.Arg117His ABCC7 p.Arg117His Current laboratory guidelines state that intron 8 polyT status should be assessed as a reflex test when R117H is detected, since clarifying the polyT status in individuals with R117H can help delineate the range of potential phenotype (Grody et al. 2001; Watson et al. 2004). Login to comment 145 ABCC7 p.Arg117His Because the 5T variant is associated with a significant reduction in functional CFTR protein, it has the potential to be clinically significant not only in cis with another variant (like R117H) but also as a stand-alone mutation. Login to comment 153 ABCC7 p.Arg117His ABCC7 p.Arg117His RECOMMENDATION 8: THE R117H/POLY T and 5T/TG TRACT ALLELES If a client is found to carry an R117H mutation, it is important to ensure the testing laboratory performs reflex testing for poly T status along with studies to determine the cis/trans orientation of the poly T alleles. Login to comment 154 ABCC7 p.Arg117His In the absence of an R117H mutation, assessment of the intron 8 poly T or TG tracts is not recommended for routine CF carrier testing. Login to comment 172 ABCC7 p.Trp1282* ABCC7 p.Gly542* G542X, W1282X II Cause structural alterations to the CFTR protein and prevent it from moving to the cell surface. Login to comment 174 ABCC7 p.Gly551Asp G551D IV CFTR reaches the cell surface but chloride secretion is reduced. Login to comment 175 ABCC7 p.Arg334Trp ABCC7 p.Arg347Pro R334W, R347P V Lead to a quantitative defect in the amount of CFTR protein that reaches the cell surface due to decreased stability of mRNA. Login to comment