ClinVar Miner

Submissions for variant NM_000492.4(CFTR):c.613C>T (p.Pro205Ser) (rs121908803)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
CFTR2 RCV000056400 SCV000071514 pathogenic Cystic fibrosis 2017-03-17 reviewed by expert panel research
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000056400 SCV000697038 pathogenic Cystic fibrosis 2016-07-20 criteria provided, single submitter clinical testing Variant summary: The CFTR c.613C>T (p.Pro205Ser) variant involves the alteration of a conserved nucleotide. 5/5 in silico tools predict a damaging outcome for this variant. Pro205 is highly conserved across species and is located in the ABC transporter type 1, transmembrane domain of the cystic fibrosis transmembrane conductance regulator protein. Functional studies have shown that P205S severely impairs chloride conductance, and P205S does not mature and thus does not properly localize to the plasma membrane. This variant was not found in 121408 control chromosomes, but has been cited in both PS- and PI-CF patients reported in the literature. In addition, one reputable database classified this variant as pathogenic. Taken together, this variant is classified as Pathognenic.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000724656 SCV000700811 pathogenic not provided 2017-05-17 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000724656 SCV000885185 pathogenic not provided 2018-06-26 criteria provided, single submitter clinical testing The CFTR c.613C>T; p.Pro205Ser variant (rs121908803) is reported in individuals with cystic fibrosis, commonly associated with the pancreatic sufficient form (CFTR2 database, Chillon 1993, Sheridan 2011, Sosnay 2013). Functional studies of the variant protein show decreased protein maturation and severely impaired chloride channel function (Sheppard 1996). This variant is reported as pathogenic in ClinVar (Variation ID: 54026), and it is found in the general population with a low overall allele frequency of 0.0004% (1/246192 alleles) in the Genome Aggregation Database. The proline at codon 205 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Based on available information, this variant is considered to be moderately pathogenic. REFERENCES CFTR2 database: Chillon M et al. Identification of a new missense mutation (P205S) in the first transmembrane domain of the CFTR gene associated with a mild cystic fibrosis phenotype. Hum Mol Genet. 1993 Oct;2(10):1741-2. Sheppard DN et al. Contribution of proline residues in the membrane-spanning domains of cystic fibrosis transmembrane conductance regulator to chloride channel function. J Biol Chem. 1996 Jun 21;271(25):14995-5001. Sheridan MB et al. CFTR transcription defects in pancreatic sufficient cystic fibrosis patients with only one mutation in the coding region of CFTR. J Med Genet. 2011 Apr;48(4):235-41. Sosnay PR et al. Defining the disease liability of variants in the cystic fibrosis transmembrane conductance regulator gene. Nat Genet. 2013 Oct;45(10):1160-7.
Mendelics RCV000056400 SCV000886189 pathogenic Cystic fibrosis 2018-11-05 criteria provided, single submitter clinical testing
Baylor Genetics RCV001004442 SCV001163487 pathogenic Cystic fibrosis; Congenital bilateral aplasia of vas deferens from CFTR mutation criteria provided, single submitter clinical testing
CFTR-France RCV000056400 SCV001169322 pathogenic Cystic fibrosis 2018-01-29 criteria provided, single submitter curation
Invitae RCV000056400 SCV001586988 pathogenic Cystic fibrosis 2020-10-23 criteria provided, single submitter clinical testing This sequence change replaces proline with serine at codon 205 of the CFTR protein (p.Pro205Ser). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and serine. This variant is not present in population databases (ExAC no frequency). This variant has been observed to segregate with cystic fibrosis in a family (PMID: 7505694) and it has been observed in combination with another CFTR variant in individuals affected with this condition (PMID: 7505694, 21097845, 25363320). ClinVar contains an entry for this variant (Variation ID: 54026). Experimental studies have shown that this missense change disrupts CFTR function (PMID: 23974870). For these reasons, this variant has been classified as Pathogenic.
Counsyl RCV000056400 SCV001132149 likely pathogenic Cystic fibrosis 2015-09-16 no assertion criteria provided clinical testing

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