ClinVar Miner

Submissions for variant NM_000492.3(CFTR):c.3705T>G (p.Ser1235Arg) (rs34911792)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000079000 SCV000110869 benign not specified 2012-07-24 criteria provided, single submitter clinical testing
Invitae RCV000029527 SCV000285004 benign Cystic fibrosis 2018-01-03 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000079000 SCV000304492 likely benign not specified criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000079000 SCV000538671 benign not specified 2018-09-14 criteria provided, single submitter clinical testing The p.Ser1235Arg variant in CFTR is classified as benign because it has been ide ntified in 0.9% (87/10124) of Ashkenazi Jewish chromosomes and 0.7% (939/125536) of European chromosomes, including 4 homozygotes, by gnomAD (http://gnomad.broa dinstitute.org). ACMG/AMP Criteria applied: BA1.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000079000 SCV000601104 likely benign not specified 2017-01-27 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000755234 SCV000602980 uncertain significance not provided 2017-05-26 criteria provided, single submitter clinical testing The CFTR c.3705T>G, p.Ser1235Arg variant (rs34911792) is historically considered to be mildly pathogenic due to its prevalence in patients diagnosed with mild respiratory disorders (Rene 2011) or chronic pancreatitis (Hamoir 2013, Steiner 2011, Weiss 2005). However, genotype-phenotype studies indicate that the variant is observed at similar frequencies between affected and asymptomatic individuals (LaRusch 2014, Monaghan 2000, Rene 2011, Sosnay 2013). Functional studies also indicate no defect in CFTR maturation or chloride transport activity (Sosnay 2013, Van Goor 2014). The variant is listed in ClinVar (Variation ID: 35872), and observed in the general population at an overall frequency of 0.5% (1368/273990 alleles, 4 homozygotes) in the Genome Aggregation Database. The serine at residue 1235 is moderately conserved, and computational algorithms (Align GVGD, Mutation Taster, PolyPhen-2, SIFT) predict that the variant has minimal impact on the protein. Current evidence indicates that this variant, when present with a pathogenic CFTR variant on the opposite chromosome, is not associated with classic cystic fibrosis. However, it remains uncertain whether it may contribute to the clinical phenotype in individuals with milder CFTR-related disease (e.g., an isolated presentation of pancreatitis, congenital bilateral absence of the vas deferens, or mild lung disease). References: Hamoir C et al. Clinical and morphological characteristics of sporadic genetically determined pancreatitis as compared to idiopathic pancreatitis: higher risk of pancreatic cancer in CFTR variants. Digestion. 2013; 87(4):229-39. LaRusch J et al. Mechanisms of CFTR functional variants that impair regulated bicarbonate permeation and increase risk for pancreatitis but not for cystic fibrosis. PLoS Genet. 2014; 10(7):e1004376. Monaghan K et al. Frequency and clinical significance of the S1235R mutation in the cystic fibrosis transmembrane conductance regulator gene: results from a collaborative study. Am J Med Genet. 2000; 95(4):361-5. Rene C et al. p.Ser1235Arg should no longer be considered as a cystic fibrosis mutation: results from a large collaborative study. Eur J Hum Genet. 2011; 19(1):36-42. Sosnay PR et al. Defining the disease liability of variants in the cystic fibrosis transmembrane conductance regulator gene. Nat Genet. 2013; 45(10):1160-7. Steiner B et al Common CFTR haplotypes and susceptibility to chronic pancreatitis and congenital bilateral absence of the vas deferens. Hum Mutat. 2011; 32(8):912-20. Van Goor F et al. Effect of ivacaftor on CFTR forms with missense mutations associated with defects in protein processing or function. J Cyst Fibros. 2014; 13(1):29-36. Weiss F et al. Complete cystic fibrosis transmembrane conductance regulator gene sequencing in patients with idiopathic chronic pancreatitis and controls. Gut. 2005; 54(10):1456-60.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000755234 SCV000888089 benign not provided 2018-01-16 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000029527 SCV000052179 benign Cystic fibrosis 2013-10-29 no assertion criteria provided clinical testing
Genetic Services Laboratory, University of Chicago RCV000079000 SCV000150651 likely benign not specified no assertion criteria provided clinical testing Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed.

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