Submissions for variant NM_000492.4(CFTR):c.1624G>T (p.Gly542Ter)

gnomAD frequency: 0.00029  dbSNP: rs113993959

Total submissions: 36

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
American College of Medical Genetics and Genomics (ACMG)	RCV000007535	SCV000071394	pathogenic	Cystic fibrosis	2004-03-03	practice guideline	curation	Converted during submission to Pathogenic.
CFTR2	RCV000007535	SCV000071540	pathogenic	Cystic fibrosis	2017-03-17	reviewed by expert panel	research
Invitae	RCV000007535	SCV000074376	pathogenic	Cystic fibrosis	2024-01-29	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gly542*) in the CFTR gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CFTR are known to be pathogenic (PMID: 1695717, 7691345, 9725922). This variant is present in population databases (rs113993959, gnomAD 0.1%). This premature translational stop signal has been observed in individual(s) with cystic fibrosis (PMID: 15371902, 23974870). This variant is also known as G542X. ClinVar contains an entry for this variant (Variation ID: 7115). For these reasons, this variant has been classified as Pathogenic.
Eurofins Ntd Llc (ga)	RCV000058931	SCV000225524	pathogenic	not provided	2015-10-12	criteria provided, single submitter	clinical testing
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000058931	SCV000281000	pathogenic	not provided	2015-02-11	criteria provided, single submitter	clinical testing
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	RCV000007535	SCV000584080	pathogenic	Cystic fibrosis	2018-04-16	criteria provided, single submitter	research
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000058931	SCV000603003	pathogenic	not provided	2023-03-21	criteria provided, single submitter	clinical testing	The CFTR c.1624G>T; p.Gly542Ter variant (rs113993959) has been reported in multiple cystic fibrosis patients, associated with pancreatic insufficiency (Kerem 1990, Castaldo 1997, Loirat 1997, Hirtz 2004, Ooi 2012, Sosnay 2013, CFTR2 database). This variant is reported in ClinVar (Variation ID: 7115), and is found in the general population with an overall allele frequency of 0.03% (91/282312 alleles) in the Genome Aggregation Database. This variant induces an early termination codon and is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered to be pathogenic. References: CFTR2 database: http://cftr2.org/ Castaldo G et al. Severe liver impairment in a cystic fibrosis-affected child homozygous for the G542X mutation. Am J Med Genet. 1997 Mar 17;69(2):155-8. 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. Loirat F et al. G542X as a probable Phoenician cystic fibrosis mutation. Hum Biol. 1997 Jun;69(3):419-25. Hirtz S et al. CFTR Cl- channel function in native human colon correlates with the genotype and phenotype in cystic fibrosis. Gastroenterology. 2004 Oct;127(4):1085-95. Ooi C and Durie PR. Cystic fibrosis transmembrane conductance regulator (CFTR) gene mutations in pancreatitis. J Cyst Fibros. 2012 Sep;11(5):355-62. Sosnay PR et al. Defining the disease liability of variants in the cystic fibrosis transmembrane conductance regulator gene. Nat Genet. 2013 Oct;45(10):1160-7.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000007535	SCV000696855	pathogenic	Cystic fibrosis	2021-04-08	criteria provided, single submitter	clinical testing	Variant summary: CFTR c.1624G>T (p.Gly542X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 0.00034 in 250908 control chromosomes (gnomAD). c.1624G>T has been reported in the literature in multiple individuals affected with Cystic Fibrosis (e.g. McKone_2003, Sosnay_2013). These data indicate that the variant is very likely to be associated with disease. Sixteen ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	RCV000007535	SCV000883110	pathogenic	Cystic fibrosis	2018-11-21	criteria provided, single submitter	clinical testing
Mendelics	RCV000007535	SCV000886177	pathogenic	Cystic fibrosis	2018-11-05	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000058931	SCV000889294	pathogenic	not provided	2019-12-24	criteria provided, single submitter	clinical testing	he c.1624G>T (p.Gly542*) pathogenic variant (also known as G542X) causes the premature termination of CFTR protein synthesis. It has been reported in individuals affected with cystic fibrosis (CF) and CFTR-related disorders in the published literature (PMIDs: 12767731 (2003), 15371902 (2004), 15994263 (2005), 21416780 (2010), 22658665 (2012), 23751316 (2013), 23951356 (2013)). A functional study has shown that this variant abrogates CFTR chloride channel activity (PMID: 7522901 (1993)).
Center for Precision Medicine, Vanderbilt University Medical Center	RCV000007535	SCV000889997	pathogenic	Cystic fibrosis	2018-03-16	criteria provided, single submitter	research
Fulgent Genetics, Fulgent Genetics	RCV000763572	SCV000894411	pathogenic	Bronchiectasis with or without elevated sweat chloride 1; Cystic fibrosis; Hereditary pancreatitis; Congenital bilateral aplasia of vas deferens from CFTR mutation	2018-10-31	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000007535	SCV000915203	pathogenic	Cystic fibrosis	2017-10-25	criteria provided, single submitter	clinical testing	The CFTR c.1624G>T (p.Gly542Ter) variant is a stop-gained variant predicted to result in premature termination of the protein. The p.Gly542Ter variant, a well-described pathogenic variant, is reported at a frequency of 2.64% among a pan-ethnic population clinically diagnosed with CFTR-related disorders, and recognised as the second most common pathogenic variant after p.Phe508del (Watson et al. 2004). The p.Gly542Ter variant is one of the 23 pathogenic variants recommended by the ACMG for general population cystic fibrosis carrier screening. Across a selection of the available literature, the p.Gly542Ter variant was identified in at least 40 individuals with cystic fibrosis, including five unrelated individuals in a homozygous state, 11 unrelated individuals in a compound heterozygous state, and 24 individuals in a heterozygous state (de Gracia et al. 2005; Chavez-Saldana et al. 2010). Five of the compound heterozygotes carried p.Phe508del on the second allele (de Gracia et al. 2005). Control data were unavailable for this variant in these studies but it is reported at a frequency of 0.001860 in the European American population of the Exome Sequencing Project. Based on the evidence and the potential impact of stop-gained variants, the p.Gly542Ter variant is classified as pathogenic for CFTR-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Baylor Genetics	RCV001004463	SCV001163508	pathogenic	Cystic fibrosis; Congenital bilateral aplasia of vas deferens from CFTR mutation		criteria provided, single submitter	clinical testing
CFTR-France	RCV000007535	SCV001169439	pathogenic	Cystic fibrosis	2018-01-29	criteria provided, single submitter	curation
Ambry Genetics	RCV000007535	SCV001172924	pathogenic	Cystic fibrosis	2021-09-15	criteria provided, single submitter	clinical testing	The p.G542* pathogenic mutation (also known as c.1624G>T and 1756G>T), located in coding exon 12 of the CFTR gene, results from a G to T substitution at nucleotide position 1624. This changes the amino acid from a glycine to a stop codon within coding exon 12. This mutation, in conjunction with p.F508del, was detected in individuals with pancreatic insufficient cystic fibrosis; it was also identified in conjunction with p.R117H in one individual with pancreatic sufficient cystic fibrosis (Kristidis P et al. Am J Hum Genet. 1992;50(6):1178-1184). This mutation is associated with decreased lung function, elevated sweat chloride levels, and pancreatic insufficiency (Sosnay PR et al. Nat Genet. 2013;45(10):1160-1167). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
Myriad Genetics, Inc.	RCV000007535	SCV001193801	pathogenic	Cystic fibrosis	2019-10-18	criteria provided, single submitter	clinical testing	NM_000492.3(CFTR):c.1624G>T(G542*) is classified as pathogenic in the context of cystic fibrosis and is associated with the classic form of the disease. Sources cited for classification include the following: PMID 2397487 and 5371902. Classification of NM_000492.3(CFTR):c.1624G>T(G542*) is based on the following criteria: The variant causes a premature termination codon that is expected to be targeted by nonsense-mediated mRNA decay and is reported in individuals with the relevant phenotype. Please note: this variant was assessed in the context of healthy population screening.
CeGaT Center for Human Genetics Tuebingen	RCV000058931	SCV001246815	pathogenic	not provided	2020-01-01	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000058931	SCV001713424	pathogenic	not provided	2022-01-14	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000007535	SCV001810355	pathogenic	Cystic fibrosis	2021-07-22	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000058931	SCV002019231	pathogenic	not provided	2022-08-01	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV000007535	SCV002507331	pathogenic	Cystic fibrosis	2019-10-02	criteria provided, single submitter	clinical testing
MGZ Medical Genetics Center	RCV000007535	SCV002581093	pathogenic	Cystic fibrosis	2022-07-07	criteria provided, single submitter	clinical testing
Molecular Genetics and NGS Laboratory, Hospital Fundacion Valle Del Lili	RCV000763572	SCV004101388	pathogenic	Bronchiectasis with or without elevated sweat chloride 1; Cystic fibrosis; Hereditary pancreatitis; Congenital bilateral aplasia of vas deferens from CFTR mutation	2023-11-07	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003407294	SCV004108491	pathogenic	CFTR-related condition	2023-12-14	criteria provided, single submitter	clinical testing	The CFTR c.1624G>T variant is predicted to result in premature protein termination (p.Gly542*). This variant has been documented to cause cystic fibrosis (see for example Kerem et al. 1990. PubMed ID: 2236053; Sosnay et al. 2013. PubMed ID: 23974870). This variant is reported in 0.14% of alleles in individuals of Ashkenazi Jewish descent in gnomAD. Nonsense variants in CFTR are expected to be pathogenic. This variant is interpreted as pathogenic.
Baylor Genetics	RCV003473006	SCV004211629	pathogenic	Bronchiectasis with or without elevated sweat chloride 1	2023-10-31	criteria provided, single submitter	clinical testing
OMIM	RCV000007535	SCV000027736	pathogenic	Cystic fibrosis	1997-06-01	no assertion criteria provided	literature only
SNPedia	RCV000058931	SCV000090452	not provided	not provided		no assertion provided	not provided
GeneReviews	RCV000119041	SCV000153747	not provided	Hereditary pancreatitis		no assertion provided	literature only
GeneReviews	RCV000007535	SCV001622788	not provided	Cystic fibrosis		no assertion provided	literature only
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000058931	SCV001741338	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000058931	SCV001955890	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000058931	SCV001969623	pathogenic	not provided		no assertion criteria provided	clinical testing
Natera, Inc.	RCV001826428	SCV002080627	pathogenic	CFTR-related disorders	2017-03-17	no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV001826428	SCV002507415	pathogenic	CFTR-related disorders	2019-10-02	no assertion criteria provided	clinical testing