Submissions for variant NM_000492.4(CFTR):c.1315C>T (p.Pro439Ser)

gnomAD frequency: 0.00001  dbSNP: rs397508187

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000046271	SCV000074284	pathogenic	Cystic fibrosis	2023-11-25	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 439 of the CFTR protein (p.Pro439Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with mild / atypical cystic fibrosis, congenital absence of the vas deferens, or obstructive azoospermia (PMID: 15858154, 17413420, 24697796). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 53226). 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: 18769034). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000046271	SCV001171192	uncertain significance	Cystic fibrosis	2021-08-20	criteria provided, single submitter	clinical testing	The p.P439S variant (also known as c.1315C>T), located in coding exon 10 of the CFTR gene, results from a C to T substitution at nucleotide position 1315. The proline at codon 439 is replaced by serine, an amino acid with similar properties. This variant was reported in a 10-year-old male with a sweat chloride level of 59 mmol/L, pancreatic insufficiency, and recurrent Staphylococcus infections (Schrijver I et al. J Mol Diagn, 2005 May;7:289-99). In a patient with congenital bilateral absence of the vas deferens, this variant was detected in conjunction with a pathogenic allele (Grangeia A et al. Genet. Med., 2007 Mar;9:163-72). In vitro functional analyses showed this alteration resulted in a reduction of mature CFTR protein and chloride channel activity (Grangeia A et al. Cell. Physiol. Biochem., 2008 Jul;22:79-92). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000046271	SCV001737883	likely pathogenic	Cystic fibrosis	2023-07-15	criteria provided, single submitter	clinical testing	Variant summary: CFTR c.1315C>T (p.Pro439Ser) results in a non-conservative amino acid change located in the ABC transporter-like domain (IPR003439) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 242792 control chromosomes. c.1315C>T has been reported in the literature in compound heterozygosity with p.R668C in one comprehensively genotyped patient with mild CF (Schrijver_2005), in compound heterozygosity with p.R334W in one patient with CBAVD (Grangeia_2007), in compound heterozygosity with p.F508del in one comprehensively genotyped patient with azoospermia (Ooi_2014). Each of these patients is ascertained in the context of the broad phenotypic spectrum of CF and related disorders. These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in approximately 50% reduction of the amount of mature CFTR protein with predominant localization in the cytoplasm, and a significantly reduced cAMP-dependent anion conductance in an in-vitro experimental system (Grangeia_2008). The following publications have been ascertained in the context of this evaluation (PMID: 18769034, 17413420, 24697796, 25735457, 15858154, 29216686). Multiple submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 (P/LP, n=3; VUS, n=1). Some submitters cite overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Genome-Nilou Lab	RCV000046271	SCV001822046	likely pathogenic	Cystic fibrosis	2021-07-22	criteria provided, single submitter	clinical testing
DASA	RCV000046271	SCV002073743	likely pathogenic	Cystic fibrosis	2022-02-05	criteria provided, single submitter	clinical testing	The c.1315C>T;p.(Pro439Ser) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 53226; PMID: 15858154; 17413420) - PS4_moderate. Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product (PMID: 18769034) - PS3_supporting. The variant is present at low allele frequencies population databases (rs397508187 – gnomAD 0.00006573%; ABraOM 0.000854 frequency - http://abraom.ib.usp.br/) - PM2_supporting. The p.(Pro439Ser) was detected in trans with a pathogenic variant (PMID: 15858154; 17413420) - PM3. Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3. In summary, the currently available evidence indicates that the variant is likely pathogenic.
Baylor Genetics	RCV003473448	SCV004213255	likely pathogenic	Bronchiectasis with or without elevated sweat chloride 1	2024-01-18	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV003476940	SCV004221657	likely pathogenic	not provided	2023-08-09	criteria provided, single submitter	clinical testing	The CFTR c.1315C>T (p.Pro439Ser) variant has been reported in the published literature in along with another CFTR variant in an individual with cystic fibrosis (PMID: 15858154 (2005)). This variant has been reported along with other CFTR variants in individuals with CFTR related disorders including azoospermia (PMID: 24697796 (2014)), congenital bilateral absence of the vas deferens (CBAVD)(PMID: 17413420 (2007)) and pancreatitis (CFTR-France (https://cftr.iurc.montp.inserm.fr/)). Published functional studies showed that this variant results in reduced levels of mature CFTR protein and defective trafficking to the cell membrane (PMID: 18769034 (2008)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Based on the available information, this variant is classified as likely pathogenic.
Mayo Clinic Laboratories, Mayo Clinic	RCV003476940	SCV004226573	likely pathogenic	not provided	2023-03-22	criteria provided, single submitter	clinical testing	PP3, PM2, PM3, PS4_moderate