Submissions for variant NM_000492.4(CFTR):c.1654C>T (p.Gln552Ter)

dbSNP: rs76554633

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
CFTR2	RCV000007622	SCV000071547	pathogenic	Cystic fibrosis	2017-03-17	reviewed by expert panel	research
Mendelics	RCV000007622	SCV000886256	pathogenic	Cystic fibrosis	2018-11-05	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000007622	SCV001193806	pathogenic	Cystic fibrosis	2019-11-12	criteria provided, single submitter	clinical testing	NM_000492.3(CFTR):c.1654C>T(Q552*) 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 1709778, 7504969 and 23974870. Classification of NM_000492.3(CFTR):c.1654C>T(Q552*) 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.‚Äã
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000007622	SCV001554580	pathogenic	Cystic fibrosis	2021-03-31	criteria provided, single submitter	clinical testing	Variant summary: CFTR c.1654C>T (p.Gln552X) 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. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 250858 control chromosomes. c.1654C>T has been reported in the literature in multiple individuals affected with Cystic Fibrosis (example, Sosnay_2013). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories and an expert panel (CFTR2) have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000007622	SCV001588424	pathogenic	Cystic fibrosis	2019-11-22	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in CFTR are known to be pathogenic (PMID: 1695717, 7691345, 9725922). This sequence change creates a premature translational stop signal (p.Gln552*) in the CFTR gene. It is expected to result in an absent or disrupted protein product. This variant has been observed in many individuals affected with cystic fibrosis (PMID: 1709778, 18456578, 23974870, 25910067). ClinVar contains an entry for this variant (Variation ID: 7201). This variant is not present in population databases (ExAC no frequency).
Ambry Genetics	RCV000007622	SCV002704700	pathogenic	Cystic fibrosis	2022-07-27	criteria provided, single submitter	clinical testing	The p.Q552* pathogenic mutation (also known as c.1654C>T), located in coding exon 12 of the CFTR gene, results from a C to T substitution at nucleotide position 1654. This changes the amino acid from a glutamine to a stop codon within coding exon 12. In one study, this mutation was found in a patient with cystic fibrosis and pancreatic insufficiency (Devoto et al. Am J Hum Genet 1991;48: 1127). This pathogenic mutation is associated with elevated sweat chloride levels, pancreatic insufficiency, and decreased lung function (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.
PreventionGenetics, part of Exact Sciences	RCV001826445	SCV004118753	pathogenic	CFTR-related disorder	2023-03-28	criteria provided, single submitter	clinical testing	The CFTR c.1654C>T variant is predicted to result in premature protein termination (p.Gln552*). This variant has been reported in multiple individuals with cystic fibrosis and is associated with elevated sweat chloride levels, pancreatic insufficiency, and decreased lung function (Devoto et al. 1991. PubMed ID: 1709778, Sosnay et al. 2013. PubMed ID: 23974870). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Nonsense variants in CFTR are expected to be pathogenic. This variant is interpreted as pathogenic.
Baylor Genetics	RCV003473042	SCV004213399	pathogenic	Bronchiectasis with or without elevated sweat chloride 1	2023-09-05	criteria provided, single submitter	clinical testing
OMIM	RCV000007622	SCV000027823	pathogenic	Cystic fibrosis	1993-01-01	no assertion criteria provided	literature only
Natera, Inc.	RCV001826445	SCV002080637	pathogenic	CFTR-related disorder	2017-03-17	no assertion criteria provided	clinical testing