Submissions for variant NM_000492.4(CFTR):c.1679G>C (p.Arg560Thr)

gnomAD frequency: 0.00002  dbSNP: rs80055610

Total submissions: 22

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
American College of Medical Genetics and Genomics (ACMG)	RCV000007533	SCV000071397	pathogenic	Cystic fibrosis	2004-03-03	practice guideline	curation	Converted during submission to Pathogenic.
CFTR2	RCV000007533	SCV000071524	pathogenic	Cystic fibrosis	2017-03-17	reviewed by expert panel	research
Labcorp Genetics (formerly Invitae), Labcorp	RCV000007533	SCV000074427	pathogenic	Cystic fibrosis	2024-06-04	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with threonine, which is neutral and polar, at codon 560 of the CFTR protein (p.Arg560Thr). This variant is present in population databases (rs80055610, gnomAD 0.005%). This missense change has been observed in individual(s) with cystic fibrosis (PMID: 15371902, 23974870). 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: 7113). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects CFTR function (PMID: 23974870). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000224789	SCV000281159	pathogenic	not provided	2015-02-11	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000780134	SCV000917179	pathogenic	not specified	2018-03-13	criteria provided, single submitter	clinical testing	Variant summary: CFTR c.1679G>C (p.Arg560Thr) results in a non-conservative amino acid change located in the ABC transporter-like and AAA+ ATPase domains of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. Several computational tools predict a significant impact on normal splicing: four predict the variant abolishes a 5' splicing donor site. These splicing predictions have yet to be confirmed by functional studies, however studies assessing the variant effect at the protein level have shown a defective glycosylation/maturation and chloride conductance (Van Goor 2013, Sosnay 2013). The variant allele was found at a frequency of 1.7e-05 in 293912 control chromosomes. The c.1679G>C variant has been reported in the literature in numerous individuals affected with Classic Cystic Fibrosis and is considered a common pathogenic mutation (see e.g. McKone 2003, Sosnay 2013). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and all classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Johns Hopkins Genomics, Johns Hopkins University	RCV000007533	SCV000992330	pathogenic	Cystic fibrosis	2019-03-04	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV001004262	SCV001163138	pathogenic	Cystic fibrosis; Congenital bilateral aplasia of vas deferens from CFTR mutation		criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000007533	SCV001193945	pathogenic	Cystic fibrosis	2019-12-04	criteria provided, single submitter	clinical testing	NM_000492.3(CFTR):c.1679G>C(R560T) 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. Classification of NM_000492.3(CFTR):c.1679G>C(R560T) 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
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000007533	SCV001470740	pathogenic	Cystic fibrosis	2024-07-22	criteria provided, single submitter	clinical testing	The CFTR c.1679G>C; p.Arg560Thr variant (rs80055610) is known to cause cystic fibrosis (CF) when combined with another CF-causing variant and is associated with pancreatic insufficiency (CFTR2 database, SickKids CFTR database, Watson 2004). This variant has been reported as pathogenic by several laboratories in ClinVar (Variation ID: 7113) and is observed on only six chromosomes (6/250518 alleles) in the Genome Aggregation Database. Functional analyses of this variant demonstrate mRNA splicing defects and a marked reduction in translation of mature CFTR protein (Kerem 1990, van Goor 2014). Based on available information, this variant is considered pathogenic. References: CFTR2 database: https://cftr2.org SickKids CFTR database: http://www.genet.sickkids.on.ca Kerem B et al. Identification of mutations in regions corresponding to the two putative nucleotide (ATP)-binding folds of the cystic fibrosis gene. Proc Natl Acad Sci U S A. 1990 Nov;87(21):8447-51. PMID: 2236053 van Goor F et al. Effect of ivacaftor on CFTR forms with missense mutations associated with defects in protein processing or function. J Cyst Fibros. 2014 Jan;13(1):29-36. PMID: 23891399 Watson M et al. Cystic fibrosis population carrier screening: 2004 revision of American College of Medical Genetics mutation panel. Genet Med. 2004 Sep-Oct;6(5):387-91. PMID: 15371902
Mayo Clinic Laboratories, Mayo Clinic	RCV000224789	SCV001713429	pathogenic	not provided	2020-06-10	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV000007533	SCV002507347	pathogenic	Cystic fibrosis	2020-02-07	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000007533	SCV002714483	pathogenic	Cystic fibrosis	2024-07-02	criteria provided, single submitter	clinical testing	The c.1679G>C pathogenic mutation (also known as p.R560T), located in coding exon 12 of the CFTR gene, results from a G to C substitution at nucleotide position 1679. The amino acid change results in arginine to threonine at codon 560, an amino acid with similar properties. However, this change occurs in the last base pair of coding exon 12, which makes it likely to have some effect on normal mRNA splicing. This pathogenic mutation was first reported in a cohort of individuals with cystic fibrosis (Kerem BS et al. Proc. Natl. Acad. Sci. U.S.A., 1990 Nov;87:8447-51). Functional in vitro studies found that cells carrying this pathogenic mutation had no to very little chloride conduction; in addition, this pathogenic mutation is associated with high sweat chloride levels and pancreatic insufficiency Sosnay PR et al. Nat. Genet., 2013 Oct;45:1160-7; Van Goor F et al. J. Cyst. Fibros., 2014 Jan;13:29-36). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Fulgent Genetics, Fulgent Genetics	RCV002504762	SCV002810401	pathogenic	Bronchiectasis with or without elevated sweat chloride 1; Cystic fibrosis; Hereditary pancreatitis; Congenital bilateral aplasia of vas deferens from CFTR mutation	2024-04-03	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV001831521	SCV004113268	pathogenic	CFTR-related disorder	2022-09-23	criteria provided, single submitter	clinical testing	The CFTR c.1679G>C variant is predicted to result in the amino acid substitution p.Arg560Thr. This variant has been reported in numerous individuals with cystic fibrosis (Kerem et al. 1990. PubMed ID: 2236053; Castellani et al. 2008. PubMed ID: 18456578). This variant is reported in 0.0053% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/7-117227887-G-C). This variant is interpreted as pathogenic.
Baylor Genetics	RCV003473005	SCV004213262	pathogenic	Bronchiectasis with or without elevated sweat chloride 1	2024-03-30	criteria provided, single submitter	clinical testing
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	RCV001831521	SCV005900693	pathogenic	CFTR-related disorder	2023-12-15	criteria provided, single submitter	clinical testing	The c.1679G>C (p.Arg560Thr) variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. Multiple splice prediction tools suggest this variant is likely to interfere with normal splicing. This is a known Pathogenic variant that has been previously reported as a compound heterozygous or homozygous change in individuals with cystic fibrosis (PMID: 12767731, 15371902, 23974870). Functional studies have demonstrated that the c.1679G>C (p.Arg560Thr) variant results in altered mRNA splicing, decreased levels of translated mRNA, and impaired protein function (PMID: 2236053, 23974870, 23891399). This variant is present in the heterozygous state in the gnomAD population database at a frequency of 0.002% (6/250518), and is absent in the homozygous state, thus is presumed to be rare. Based on the available evidence, c.1679G>C (p.Arg560Thr) is classified as Pathogenic.
OMIM	RCV000007533	SCV000027734	pathogenic	Cystic fibrosis	1990-11-01	no assertion criteria provided	literature only
GeneReviews	RCV000007533	SCV001622791	not provided	Cystic fibrosis		no assertion provided	literature only
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000224789	SCV001740188	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000224789	SCV001968669	pathogenic	not provided		no assertion criteria provided	clinical testing
Natera, Inc.	RCV001831521	SCV002080644	pathogenic	CFTR-related disorder	2017-03-17	no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV001831521	SCV002507431	pathogenic	CFTR-related disorder	2020-02-07	no assertion criteria provided	clinical testing