ClinVar Miner

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

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000046868 SCV000074881 uncertain significance Cystic fibrosis 2019-12-18 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 reported with a second CFTR variant in an individual with congenital bilateral aplasia of the vas deferens (PMID: 10200050), and as a single heterozygous variant in individuals with non-obstructive azoospermia and chronic bronchitis, as well as in an unaffected control (PMID: 16128988, 9921909, 24451227). ClinVar contains an entry for this variant (Variation ID: 53720). Experimental studies have shown that this missense change does not affect CFTR ion channel activity at 21-degrees Celsius (C), but that it has a mild functional defect at 35-degrees C (PMID: 11278813). In summary, this variant is a rare missense change with a mild effect on protein function. It has been reported in both the population and affected individuals, but the available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Integrated Genetics/Laboratory Corporation of America 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 not specified 2019-02-14 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 alleles 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: http://www.genet.sickkids.on.ca/cftr/MutationDetailPage.external?sp=696 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 Insufficient evidence

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