ClinVar Miner

Submissions for variant NM_000492.4(CFTR):c.3468G>T (p.Leu1156Phe) (rs139729994)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000538933 SCV000625745 likely benign Cystic fibrosis 2020-11-14 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp 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
Ambry Genetics RCV001020371 SCV001181844 uncertain significance Inborn genetic diseases 2020-09-04 criteria provided, single submitter clinical testing The c.3468G>T variant (also known as p.L1156F), located in coding exon 21 of the CFTR gene, results from a G to T substitution at nucleotide position 3468. The amino acid change results in leucine to phenylalanine at codon 1156, an amino acid with highly similar properties. However, this change occurs in the last base pair of coding exon 21, which makes it likely to have some effect on normal mRNA splicing. This variant has been reported in multiple Japanese individuals with idiopathic, familial, hereditary, and alcoholic pancreatitis, including one individual with alcoholic pancreatitis who was homozygous for this alteration (Nakano E, Dig. Dis. Sci. 2015 May; 60(5):1297-307; Kondo S, Am. J. Physiol. Gastrointest. Liver Physiol. 2015 Aug; 309(4):G260-9). This amino acid position is well conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Illumina Clinical Services Laboratory,Illumina RCV001163786 SCV001325859 uncertain significance CFTR-related disorders 2017-04-27 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Natera, Inc. RCV000538933 SCV001456000 uncertain significance Cystic fibrosis 2018-05-29 no assertion criteria provided clinical testing

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