Submissions for variant NM_000492.4(CFTR):c.859A>T (p.Asn287Tyr)

gnomAD frequency: 0.00001  dbSNP: rs397508804

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003478990	SCV000697049	uncertain significance	not specified	2024-09-20	criteria provided, single submitter	clinical testing	Variant summary: CFTR c.859A>T (p.Asn287Tyr) results in a non-conservative amino acid change located in the ABC transporter type 1, transmembrane domain (IPR011527) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.4e-05 in 252260 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.859A>T has been reported in the literature in the compound heterozygous state together with p.Phe508del in an individual with a mild form of Cystic Fibrosis (Shrimpton_1997) and in the heterozygous state in two individuals with with idiopathic chronic pancreatitis (Chang_2007). The variant has also been observed in 2 additional patients: one referred for genetic testing for chronic pancreatitis, and the other was asymptomatic but had a 1st cousin with CF (internal LCA data). Both patients also tested positive for c.2052dupA (p.Gln685ThrfsX4; phase is unknown), a mutation known to be associated with pancreatic insufficient CF. The UMD database also 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; phase not specified), suggesting that c.859A>T (p.Asn287Tyr) may not be the cause of CF in this patient if the two pathogenic variants (i.e. 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). At least one publication reports experimental evidence evaluating an impact on protein function (Silvis_2003). In these experiments, the variant did not exhibit a folding defect, as evidenced by similar maturation kinetics to the wild type CFTR protein. However, there was roughly 50% of the variant protein located 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 the variant were similar to those of the wild type. Biotinylation experiments showed that the variant protein was internalized approximately twice as fast as wild type CFTR, which is expected to alter its distribution between the plasma membrane and intracellular compartments, reducing its expression at the cell surface. The following publications have been ascertained in the context of this evaluation (PMID: 34740355, 17539902, 9401006, 12529365, 16339147, 25735457). ClinVar contains an entry for this variant (Variation ID: 54069). Based on the evidence outlined above, the variant was classified as uncertain significance.
Counsyl	RCV000577376	SCV000788445	uncertain significance	Cystic fibrosis	2017-03-15	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV001004240	SCV001163116	likely pathogenic	Cystic fibrosis; Congenital bilateral aplasia of vas deferens from CFTR mutation		criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000577376	SCV001822024	uncertain significance	Cystic fibrosis	2021-07-22	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000577376	SCV002307517	uncertain significance	Cystic fibrosis	2021-11-14	criteria provided, single submitter	clinical testing	This sequence change replaces asparagine, which is neutral and polar, with tyrosine, which is neutral and polar, at codon 287 of the CFTR protein (p.Asn287Tyr). This variant is present in population databases (rs397508804, gnomAD 0.003%). This missense change has been observed in individual(s) with cystic fibrosis (PMID: 9401006). ClinVar contains an entry for this variant (Variation ID: 54069). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). Experimental studies have shown that this missense change affects CFTR function (PMID: 12529365). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Institute of Human Genetics, University of Leipzig Medical Center	RCV000577376	SCV002574061	likely pathogenic	Cystic fibrosis	2022-09-05	criteria provided, single submitter	curation	This variant was identified in 1 patient with a clinically confirmed diagnosis of cystic fibrosis. The variant was classified in the context of a project re-classifying variants in the German Cystic Fibrosis Registry (Muko.e.V.). Link: https://www.muko.info/angebote/qualitaetsmanagement/register/cf-einrichtungen/mukoweb. Criteria applied: PS3_MOD, PM2_SUP, PM3, PP3
Ambry Genetics	RCV000577376	SCV002679925	uncertain significance	Cystic fibrosis	2025-01-16	criteria provided, single submitter	clinical testing	The p.N287Y variant (also known as c.859A>T), located in coding exon 7 of the CFTR gene, results from an A to T substitution at nucleotide position 859. The asparagine at codon 287 is replaced by tyrosine, an amino acid with dissimilar properties. This alteration was identified with Delta F508 in an individual with a clinical diagnosis of cystic fibrosis (Shrimpton AE et al. Hum Mutat, 1997;10:436-42). In vitro studies showed CFTR protein harboring N287Y has normal maturation, cell surface targeting, and channel gating. However, this variant increased internalization of the protein, leading to reduced expression on the cell surface (Silvis MR et al. J Biol Chem, 2003 Mar;278:11554-60). Additionally, this alteration was identified in an individual diagnosed with idiopathic chronic pancreatitis (Chang MC et al. Clin Genet, 2007 Jun;71:530-9). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear.
Baylor Genetics	RCV003474621	SCV004213287	likely pathogenic	Bronchiectasis with or without elevated sweat chloride 1	2024-01-15	criteria provided, single submitter	clinical testing
GeneDx	RCV004589537	SCV005078884	uncertain significance	not provided	2023-08-04	criteria provided, single submitter	clinical testing	Published functional studies suggest a damaging effect: increased endocytic trafficking and lower cell-surface density, but no effect on biosynthesis and targeting to the cell surface (PMID: 12529365); In silico analysis supports that this missense variant does not alter protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25735457, 26003067, 24561283, 19810821, 17235394, 16339147, 16049310, 17539902, 25404111, 22138491, 28603918, 17098482, 9401006, 12529365)
ClinVar Staff, National Center for Biotechnology Information (NCBI)	RCV000577376	SCV000679177	not provided	Cystic fibrosis		no assertion provided	literature only
Natera, Inc.	RCV000577376	SCV001454033	uncertain significance	Cystic fibrosis	2020-09-16	no assertion criteria provided	clinical testing