Submissions for variant NM_000492.4(CFTR):c.1675G>A (p.Ala559Thr)

gnomAD frequency: 0.00006  dbSNP: rs75549581

Total submissions: 18

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
CFTR2	RCV000007543	SCV000071496	pathogenic	Cystic fibrosis	2017-03-17	reviewed by expert panel	research
Eurofins Ntd Llc (ga)	RCV000521321	SCV000331552	pathogenic	not provided	2018-02-22	criteria provided, single submitter	clinical testing
GeneDx	RCV000521321	SCV000617532	pathogenic	not provided	2017-09-26	criteria provided, single submitter	clinical testing	The A559T variant in the CFTR gene has been reported previously in individuals with cystic fibrosis (Cutting et al., 1990; Keyeux et al., 2003). It is reported as pathogenic in ClinVar but additional evidence is not available (SCV000071496.3, SCV000225523.3, SCV000331552.2, SCV000485203.1; Landrum et al., 2016). Functional studies indicate that cells expressing the A599T variant have a low level of mature CFTR and do not have chloride transport ability (Van Goor et al., 2014). The A559T variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). The A559T variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. Missense variants in nearby residues (including L558S, R560K, R560T, R560S, A561E, V562I, V562L) have been reported in the Human Gene Mutation Database in association with cystic fibrosis (Stenson et al., 2014), supporting the functional importance of this region of the protein. We interpret A559T as a pathogenic variant.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000007543	SCV000696861	pathogenic	Cystic fibrosis	2016-06-30	criteria provided, single submitter	clinical testing	Variant summary: The CFTR c.1675G>A (p.Ala559Thr) variant involves the alteration of a conserved nucleotide. Variant is located in the ABC transporter-like domain, P-loop containing nucleoside triphosphate hydrolase domain, and the AAA+ATP domain in the protein. 5/5 in silico tools predict a damaging outcome for this variant. This variant was found in 2/120302 control chromosomes at a frequency of 0.0000166, which does not exceed the estimated maximal expected allele frequency of a pathogenic CFTR variant (0.0129603). This variant has been reported in many affected individuals worldwide and multiple functional studies showed that variant lead to sever defect in CFTR processing and lead to non-detectable level of chloride transport. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Mendelics	RCV000007543	SCV000886196	pathogenic	Cystic fibrosis	2018-11-05	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000521321	SCV000888069	pathogenic	not provided	2016-08-12	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV001004261	SCV001163137	pathogenic	Cystic fibrosis; Congenital bilateral aplasia of vas deferens from CFTR mutation		criteria provided, single submitter	clinical testing
CFTR-France	RCV000007543	SCV001169401	pathogenic	Cystic fibrosis	2018-01-29	criteria provided, single submitter	curation
Myriad Genetics, Inc.	RCV000007543	SCV001194165	pathogenic	Cystic fibrosis	2019-11-11	criteria provided, single submitter	clinical testing	NM_000492.3(CFTR):c.1675G>A(A559T) is classified as pathogenic in the context of cystic fibrosis and is associated with the classic form of disease. Sources cited for classification include the following: PMID 23974870, 18456578 and 1695717. Classification of NM_000492.3(CFTR):c.1675G>A(A559T) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.‚Äã
Labcorp Genetics (formerly Invitae), Labcorp	RCV000007543	SCV001587902	pathogenic	Cystic fibrosis	2024-12-05	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 559 of the CFTR protein (p.Ala559Thr). This variant is present in population databases (rs75549581, gnomAD 0.02%). This missense change has been observed in individual(s) with cystic fibrosis (PMID: 1695717, 7668304, 9150159, 9950364, 12007216, 18456578, 23670503, 23974870, 25489051). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 7123). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt CFTR protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects CFTR function (PMID: 1712898, 23891399, 23974870). For these reasons, this variant has been classified as Pathogenic.
Revvity Omics, Revvity	RCV000521321	SCV002019220	pathogenic	not provided	2022-08-23	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000007543	SCV002714610	pathogenic	Cystic fibrosis	2022-07-25	criteria provided, single submitter	clinical testing	The p.A559T pathogenic mutation (also known as c.1675G>A), located in coding exon 12 of the CFTR gene, results from a G to A substitution at nucleotide position 1675. The alanine at codon 559 is replaced by threonine, an amino acid with similar properties. In one study, this mutation was detected in the homozygous state in an individual with poor feeding, cough, sudden weight loss, pancreatic insufficiency, and elevated sweat chloride levels; the individual's parents were confirmed carriers (McDowell T et al. Am. J. Hum. Genet., 1995 Sep;57:734). This mutation is associated with elevated sweat chloride levels and pancreatic insufficiency (Sosnay PR et al. Nat. Genet., 2013 Oct;45:1160-7). In addition, in vitro functional studies showed reduced mature CFTR protein levels as well as undetectable chloride conductance (Gregory RJ et al. Mol. Cell. Biol., 1991 Aug;11:3886-93; Van Goor F et al. J. Cyst. Fibros., 2014 Jan;13:29-36; Sosnay PR et al. Nat. Genet., 2013 Oct;45:1160-7). Based on available evidence, this alteration is interpreted as a disease-causing mutation.
Fulgent Genetics, Fulgent Genetics	RCV002476941	SCV002781665	pathogenic	Bronchiectasis with or without elevated sweat chloride 1; Cystic fibrosis; Hereditary pancreatitis; Congenital bilateral aplasia of vas deferens from CFTR mutation	2024-06-04	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003473010	SCV004213284	pathogenic	Bronchiectasis with or without elevated sweat chloride 1	2024-03-14	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000521321	SCV005046897	pathogenic	not provided	2023-01-31	criteria provided, single submitter	clinical testing
OMIM	RCV000007543	SCV000027744	pathogenic	Cystic fibrosis	1990-07-26	no assertion criteria provided	literature only
Natera, Inc.	RCV001826429	SCV002080642	pathogenic	CFTR-related disorder	2017-03-17	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV001826429	SCV004116559	pathogenic	CFTR-related disorder	2024-09-05	no assertion criteria provided	clinical testing	The CFTR c.1675G>A variant is predicted to result in the amino acid substitution p.Ala559Thr. This variant has been reported to be causative for Cystic Fibrosis (referred to as G1807>A in Cutting et al. 1990. PubMed ID: 1695717; Sosnay et al. 2013. PubMed ID: 23974870; www.CFTR2.org). In vitro functional studies show this variant affects CFTR protein function (Van Goor et al. 2014. PubMed ID: 23891399). This variant is reported in 0.024% of alleles in individuals of African descent in gnomAD. This variant is interpreted as pathogenic.