ClinVar Miner

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

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000046868 SCV000074881 uncertain significance Cystic fibrosis 2017-08-30 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

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