ClinVar Miner

Submissions for variant NM_000492.3(CFTR):c.859A>T (p.Asn287Tyr) (rs397508804)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Integrated Genetics/Laboratory Corporation of America RCV000586772 SCV000697049 uncertain significance not provided 2016-05-25 criteria provided, single submitter clinical testing Variant summary: The CFTR c.859A>T (p.Asn287Tyr) variant involves the alteration of a conserved nucleotide located within cytoplasmic loop 2. 4/5 in silico tools predict a damaging outcome for this variant This variant was found in 1/115258 control chromosomes at a frequency of 0.0000087, which does not exceed the estimated maximal expected allele frequency of a pathogenic CFTR variant (0.0129603). The literature cites the variant in 1 individual with a mild form of CF and 2 patients with idiopathic chronic pancreatitis (Shrimpton et al., 1997; Chang et al., 2007). The variant was identified in 2 additional patients; one was referred for genetic testing for CP, the other one had no symptoms but had a 1st cousin with CF (see communication with GC). Both patients also tested positive for c.2052dupA (p.Gln685ThrfsX4; phase is unknown) a mutation, known to be associated with pancreatic insufficient CF (internal LCA data). The UMD database reported the variant of interest in one CF patient who had c.1521_1523delCTT (p.Phe508del) on the other allele and also carried c.2052dup (p.Gln685ThrfsX4), suggesting that c.859A>T (p.Asn287Tyr) may not be the cause of CF in this patient if the two pathogenic variants, p.Gln685ThrfsX4 and p.Phe508del, were in trans. It is possible that p.Gln685ThrfsX4 may be in cis with p.Asn287Tyr given these two relatively uncommon variants (p.Gln685ThrfsX4 has an allele frequency of 2/119584 in ExAC) were found together in 3 individuals and co-segregated together in one family (internal LCA data).The N287Y mutant resides in the second intracellular loop. In the functional studies, this mutant did not exhibit a folding defect, because the N287Y and wild type CFTR proteins showed similar maturation kinetics. However, there was roughly 50% of the mutant at the plasma membrane at the steady state relative to wild type CFTR. Cholride transport was reduced in proportion to altered cell surface CFTR, but the single-channel properties of N287Y were similar to those of wild type CFTR. Biotinylation experiments showed that N287Y CFTR was internalized approximately twice as fast as wild type CFTR, which is expected to alter its distribution between the plasma membrane and intracellular compartments (Silvis et al, 2003). These findings provide evidence of disease mutations where the primary defect lies in altered kinetics of CFTR recycling at the plasma membrane, resulting in subnormal apical membrane CFTR levels. The variant has not been classified by clinical diagnostic laboratories. Overall, due to limited clinical data, this variant was classified as a "variant of uncertain significance VUS" until more information becomes available.
Counsyl RCV000577376 SCV000788445 uncertain significance Cystic fibrosis 2017-03-15 criteria provided, single submitter clinical testing
ClinVar Staff, National Center for Biotechnology Information (NCBI) RCV000577376 SCV000679177 not provided Cystic fibrosis no assertion provided literature only

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