Submissions for variant NM_000492.4(CFTR):c.2551C>T (p.Arg851Ter)

dbSNP: rs121909012

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
CFTR2	RCV000007561	SCV000071556	pathogenic	Cystic fibrosis	2017-03-17	reviewed by expert panel	research
Counsyl	RCV000007561	SCV000220911	likely pathogenic	Cystic fibrosis	2014-11-24	criteria provided, single submitter	literature only
Mendelics	RCV000007561	SCV000886220	pathogenic	Cystic fibrosis	2018-11-05	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV001004481	SCV001163526	pathogenic	Cystic fibrosis; Congenital bilateral aplasia of vas deferens from CFTR mutation		criteria provided, single submitter	clinical testing
CFTR-France	RCV000007561	SCV001169496	pathogenic	Cystic fibrosis	2018-01-29	criteria provided, single submitter	curation
Labcorp Genetics (formerly Invitae), Labcorp	RCV000007561	SCV001586222	pathogenic	Cystic fibrosis	2025-01-12	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg851*) 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 not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with congenital bilateral absence of vas deferens (PMID: 22483971). ClinVar contains an entry for this variant (Variation ID: 7141). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000007561	SCV002555916	pathogenic	Cystic fibrosis	2022-06-16	criteria provided, single submitter	clinical testing	Variant summary: CFTR c.2551C>T (p.Arg851X) 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 251312 control chromosomes (gnomAD). c.2551C>T has been reported in the literature in multiple individuals affected with Cystic Fibrosis (e.g. Sosnay_2013). These data indicate that the variant is very likely to be associated with disease. Experimental evidence evaluating an impact on protein function demonstrated the variant induced two defects: the generation of a PTC and alternative splicing of exon 15 (Hinzpeter_2012). Five ClinVar submitters including an expert panel (CFTR2) (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Ambry Genetics	RCV000007561	SCV002740658	pathogenic	Cystic fibrosis	2023-11-03	criteria provided, single submitter	clinical testing	The p.R851* pathogenic mutation (also known as c.2551C>T), located in coding exon 15 of the CFTR gene, results from a C to T substitution at nucleotide position 2551. This changes the amino acid from an arginine to a stop codon within coding exon 15. This mutation was reported in a child with severe cystic fibrosis (White MB et al. Genomics, 1991 Nov;11:778-9) and was identified cystic fibrosis cohorts (Kenková P et al. J. Cyst. Fibros., 2013 Sep;12:532-7; Soltysova A et al. Clin Respir J, 2018 Mar;12:1197-1206). This mutation is associated with elevated sweat chloride levels, pancreatic insufficiency, and a higher rate of Pseudomonas infection (Sosnay PR et al. Nat. Genet., 2013 Oct;45:1160-7). One study suggests that in addition to nonsense mediated decay, the pathogenicity of this mutation is related to an increase in exon 15 skipping (Hinzpeter A et al. Hum. Mutat., 2013 Feb;34:287-91). 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV002476942	SCV002774337	pathogenic	not provided	2021-07-23	criteria provided, single submitter	clinical testing	This nonsense variant causes the premature termination of CFTR protein synthesis. In addition, it has been reported in individuals affected with Cystic Fibrosis and Congenital Bilateral Absence of the Vas Deferens (CBAVD) in the published literature (PMID: 9439669 (1997), 28603918 (2017), 23974870 (2013), 22483971 (2012), 19202204 (2008), 17331079 (2007), 10923036 (2000)). In addition, this variant has been shown to result in exon 15 skipping (PMID: 23065710 (2013)). Based on the available information, this variant is classified as pathogenic.
Baylor Genetics	RCV003473019	SCV004213422	pathogenic	Bronchiectasis with or without elevated sweat chloride 1	2024-03-07	criteria provided, single submitter	clinical testing
OMIM	RCV000007561	SCV000027762	pathogenic	Cystic fibrosis	1991-11-01	no assertion criteria provided	literature only
Natera, Inc.	RCV001831532	SCV002080768	pathogenic	CFTR-related disorder	2017-03-17	no assertion criteria provided	clinical testing
Department of Urology, First Affiliated Hospital of Nanjing Medical University	RCV000007561	SCV004217835	pathogenic	Cystic fibrosis	2023-12-25	no assertion criteria provided	clinical testing