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

gnomAD frequency: 0.00001  dbSNP: rs121908803

Total submissions: 13

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.
Eurofins Ntd Llc (ga)	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: https://www.cftr2.org 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	2023-12-04	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 205 of the CFTR protein (p.Pro205Ser). This variant is present in population databases (rs121908803, gnomAD 0.003%). This missense change has been observed in individuals with cystic fibrosis (PMID: 7505694, 21097845, 25363320). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 54026). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt CFTR protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects CFTR function (PMID: 23974870). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000056400	SCV002657040	pathogenic	Cystic fibrosis	2020-11-24	criteria provided, single submitter	clinical testing	The p.P205S pathogenic mutation (also known as c.613C>T and 745C>T), located in coding exon 6 of the CFTR gene, results from a C to T substitution at nucleotide position 613. The proline at codon 205 is replaced by serine, an amino acid with similar properties. This mutation was first described in four individuals from two separate families who presented with respiratory symptoms, pancreatic sufficiency, congenital absence of the vas deferens (CBAVD) in one male, and no gastrointestinal features (Chillón M et al. Hum. Mol. Genet., 1993 Oct;2:1741-2). In vitro functional studies revealed that the p.P205S mutant protein had reduced CFTR protein quantity and chloride conductance (Sheppard DN et al. J. Biol. Chem., 1996 Jun;271:14995-5001; Sosnay PR et al. Nat. Genet., 2013 Oct;45:1160-7). This pathogenic mutation is associated with elevated sweat chloride levels and and the majority of individuals are pancreatic sufficient (Sosnay PR et al. Nat. Genet., 2013 Oct;45:1160-7). Based on the supporting evidence, p.P205S is classified as a disease-causing mutation.
Baylor Genetics	RCV003474612	SCV004213343	pathogenic	Bronchiectasis with or without elevated sweat chloride 1	2023-10-01	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003915014	SCV004732168	pathogenic	CFTR-related condition	2024-02-23	criteria provided, single submitter	clinical testing	The CFTR c.613C>T variant is predicted to result in the amino acid substitution p.Pro205Ser. This variant has been reported to be causative for cystic fibrosis (Chillon et al. 1993. PubMed ID: 7505694; Castellani et al. 2008. PubMed ID: 18456578; Sheridan et al. 2011. PubMed ID: 21097845; Sosnay et al. 2013. PubMed ID: 23974870). This variant is reported in 0.0029% of alleles in individuals of Latino descent in gnomAD. This variant is interpreted as pathogenic.
Counsyl	RCV000056400	SCV001132149	likely pathogenic	Cystic fibrosis	2015-09-16	no assertion criteria provided	clinical testing
Natera, Inc.	RCV001835667	SCV002078120	pathogenic	CFTR-related disorders	2017-03-17	no assertion criteria provided	clinical testing