ClinVar Miner

Submissions for variant NM_000492.3(CFTR):c.1315C>T (p.Pro439Ser) (rs397508187)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000046271 SCV000074284 likely pathogenic Cystic fibrosis 2020-07-31 criteria provided, single submitter clinical testing This sequence change replaces proline with serine at codon 439 of the CFTR protein (p.Pro439Ser). 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 reported in individuals affected with mild / atypical cystic fibrosis or congenital absence of the vas deferens (PMID: 15858154, 17413420). ClinVar contains an entry for this variant (Variation ID: 53226). Experimental studies have shown that this missense change interferes with protein maturation and localization to the cell membrane in cultured cells (PMID: 18769034). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Ambry Genetics RCV001010927 SCV001171192 uncertain significance Inborn genetic diseases 2019-08-08 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 59mmol/L, pancreatic insufficiency, and Staphylococcus infections, with overall mild pulmonary disease (Schrijver I et al. J Mol Diagn, 2005 May;7:289-99); a second disease-causing allele was not identified. In a patient with CAVD, this variant was detected in conjunction with a pathogenic allele (Grangeia A et al. Genet. Med., 2007 Mar;9:163-72) and a later functional study showed this alteration resulted in a reduction of protein levels 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 2021-06-06 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). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as likely pathogenic, and one laboratory classified the variant as uncertain significance. Both submitters cite overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Nilou-Genome Lab RCV000046271 SCV001822046 likely pathogenic Cystic fibrosis 2021-07-22 criteria provided, single submitter clinical testing

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