ClinVar Miner

Submissions for variant NM_000492.3(CFTR):c.332C>T (p.Pro111Leu) (rs140502196)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000046868 SCV000074881 uncertain significance Cystic fibrosis 2020-10-25 criteria provided, single submitter clinical testing This sequence change replaces proline with leucine at codon 111 of the CFTR protein (p.Pro111Leu). The proline residue is moderately conserved and there is a moderate physicochemical difference between proline and leucine. This variant is present in population databases (rs140502196, ExAC 0.02%). This variant has been observed in individual(s) with congenital bilateral aplasia of the vas deferens (PMID: 10200050). ClinVar contains an entry for this variant (Variation ID: 53720). ClinVar contains an entry for this variant (Variation ID: 53720). This variant has been reported to have conflicting or insufficient data to determine the effect on CFTR protein function (PMID: 11278813). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000590642 SCV000696965 uncertain significance not provided 2016-12-07 criteria provided, single submitter clinical testing Variant summary: The c.332C>T variant affects a conserved nucleotide, resulting in amino acid change from Pro to Leu. 4/5 in-silico tools predict damaging outcome for this variant. This variant is found in 9/121640 control chromosomes at a frequency of 0.000074, which does not exceed maximal expected frequency of a pathogenic allele (0.0129603). This variant has been reported in at least one CBAVD patient with another pathogenic variant in trans (N1303K, de Meeus_1998 and Steiner_2011). This variant has also been reported in one individual affected with chronic bronchitis (Bombieri_1998) and one non-obstructive infertile patient in heterozygous state, who also had azoospermia factor (AZF) gene deletion AZF (i.e. USP9Y) that may explain the infertility phenotype (Larriba_2005). One functional study showed comparable level of channel conductance, charge transport capacity, and maturation in vitro as wild-type CFTR protein (Hammerle_2001). Taken together, due to the lack of clinical information, this variant was classified as variant of unknown significance until more evidence becomes available.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000590642 SCV000857073 uncertain significance not provided 2017-09-21 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001001101 SCV001158238 uncertain significance none provided 2020-05-06 criteria provided, single submitter clinical testing The CFTR c.332C>T; p.Pro111Leu variant (rs140502196) is described in the literature in individuals with atypical cystic fibrosis (i.e. congenital bilateral absence of the vas deferens (CBAVD), isolated pulmonary disease) (Bombieri 1998, de Meeus 1998, Larriba 2005). One affected individual carried a second pathogenic variant in CFTR (de Meeus 1998); however, additional pathogenic variants were not identified in other affected individuals (Bombieri 1998, Larriba 2005). A different variant at this codon (p.Pro111Ala) exhibits altered gating kinetics (Hammerle 2001) and is reported in an individual with CBAVD who carried a pathogenic variant on the opposite allele (SickKids database). The p.Pro111Leu variant is reported in ClinVar (Variation ID: 53720) and is found in the general population with a low overall allele frequency of 0.006% (17/282480 alleles) in the Genome Aggregation Database. The proline at codon 111 is highly conserved, but computational analyses (SIFT: tolerated, PolyPhen-2: damaging) predict conflicting effects of this variant on protein structure/function. While functional studies indicate wildtype chloride channel activity at room temperature, this variant exhibits a defect in gating potential at physiological temperatures, suggesting altered activity under conditions closer to those in human tissues (Hammerle 2001). Although this variant is unlikely to be causative for classic cystic fibrosis, based on available information, we consider it uncertain whether it is pathogenic for other CFTR-related disorders. References: Link to SickKids database: Bombieri C et al. Complete mutational screening of the CFTR gene in 120 patients with pulmonary disease. Hum Genet. 1998 Dec;103(6):718-22. de Meeus A et al. Genetic findings in congenital bilateral aplasia of vas deferens patients and identification of six novel mutatations. Mutations in brief no. 138. Online. Hum Mutat. 1998;11(6):480. Hammerle MM et al. Disease-associated mutations in the extracytoplasmic loops of cystic fibrosis transmembrane conductance regulator do not impede biosynthetic processing but impair chloride channel stability. J Biol Chem. 2001 May 4;276(18):14848-54. Larriba S et al. Molecular evaluation of CFTR sequence variants in male infertility of testicular origin. Int J Androl. 2005 Oct;28(5):284-90.
CFTR-France RCV001009500 SCV001169595 pathogenic CFTR-related disorders 2015-07-03 criteria provided, single submitter curation
Ambry Genetics RCV001020001 SCV001181423 uncertain significance Inborn genetic diseases 2018-09-21 criteria provided, single submitter clinical testing The p.P111L variant (also known as c.332C>T), located in coding exon 4 of the CFTR gene, results from a C to T substitution at nucleotide position 332. The proline at codon 111 is replaced by leucine, an amino acid with similar properties. This alteration has been reported in association with congenital bilateral absence of vas deferens (de Meeus A et al. Hum. Mutat., 1998;11:480), bronchitis (Bombieri C et al. Hum. Genet., 1998 Dec;103:718-22), and non-obstructive azoospermia (Larriba S et al. Int. J. Androl., 2005 Oct;28:284-90). In vitro studies suggested a difference in channel activity between the mutant and wild type under a specific temperature condition (Hämmerle MM et al. J. Biol. Chem., 2001 May;276:14848-54). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on available evidence to date, the clinical significance of this alteration remains unclear.
Mayo Clinic Laboratories, Mayo Clinic RCV000590642 SCV001714829 uncertain significance not provided 2019-08-22 criteria provided, single submitter clinical testing
GeneDx RCV000590642 SCV001767634 uncertain significance not provided 2020-12-29 criteria provided, single submitter clinical testing Identified as being possibly associated with CFTR-related disorders, however, functional studies show that this variant only slightly reduced mutant protein biosynthesis and stability and chloride efflux ability compared to wild type (Hammerle et al., 2001), and most reports of P111L in the published literature describe individuals with non-obstructive azoospermia and chronic bronchitis who were not found to harbor a second CFTR variant in trans (Bombieri et al., 1998; Larriba et al., 2005); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 28603918, 9921909, 24451227, 24727426, 16128988, 29484681, 26277102, 11278813, 26990548, 10200050, 21520337)
Nilou-Genome Lab RCV000046868 SCV001821992 uncertain significance Cystic fibrosis 2021-07-22 criteria provided, single submitter clinical testing

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