ClinVar Miner

Submissions for variant NM_000492.3(CFTR):c.3468G>T (p.Leu1156Phe) (rs139729994)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000538933 SCV000625745 likely benign Cystic fibrosis 2017-06-07 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000589219 SCV000696970 uncertain significance not provided 2017-07-27 criteria provided, single submitter clinical testing Variant summary: The CFTR c.3468G>T (p.Leu1156Phe) variant involves the alteration of a conserved nucleotide located in the last position of exon 21. 3/5 in silico tools predict a benign outcome for this variant. 4/5 splice prediction tools predict the weakening of a canonical 5' splice donor site. Functional studies showed that CFTR expression, Cl- current, HCO3- and Cl- transport was not different from wild-type in cells expressing the variant of interest (Kondo_2015). However, Cl-/HCO3- exchange activity was reduced to 30% of the wild-type levels and two patients had higher than normal sweat chloride levels. The variant of interest in combination with a benign polymorphism (V470M) had reduced CFTR expression (60-70%) and CFTR-mediated HCO3-/Cl- transport (50-60%) compared to wild-type. These functional studies have not been validated by additional studies. This variant was found in 26/121098 control chromosomes at a frequency of 0.0002147, which does not exceed the estimated maximal expected allele frequency of a pathogenic CFTR variant (0.0062697). The variant has been reported in two publications to be statistically associated with idiopathic and alcoholic chronic pancreatitis (Kondo_2015, Nakano_2015), however the sample size in these case-control studies is small and the authors did not adjust for other likely pathogenic or pathogenic CFTR, SPINK1, and CTRC variants that were found in these cohorts. Considering all these conflicting evidence this variant is classified as a VUS until more definitive functional and clinical studies become available.
Mendelics RCV000538933 SCV000886385 uncertain significance Cystic fibrosis 2018-11-05 criteria provided, single submitter clinical testing

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