Submissions for variant NM_000492.4(CFTR):c.2537G>A (p.Trp846Ter)

gnomAD frequency: 0.00001  dbSNP: rs397508393

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
CFTR2	RCV000056367	SCV000071564	pathogenic	Cystic fibrosis	2017-03-17	reviewed by expert panel	research
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000781236	SCV000919141	pathogenic	not specified	2018-09-04	criteria provided, single submitter	clinical testing	Variant summary: CFTR c.2537G>A (p.Trp846X) 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 (eg. c.2875delG/p.Ala959fsX9 and c.3266G>A/p.Trp1089X). 4/5 computational tools predict no significant impact on normal splicing. However, one study showed that this variant caused exon skipping in about 20% transcripts (Hinzpeter_2012). The variant was absent in 246134 control chromosomes (gnomAD). The variant, c.2537G>A, has been reported in the literature in multiple individuals affected with Cystic Fibrosis (Cheadle_1993, Sosnay_2013). These data indicate that the variant is very likely to be associated with disease. One reputable database (CFTR2) has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
CFTR-France	RCV000056367	SCV001169500	pathogenic	Cystic fibrosis	2018-01-29	criteria provided, single submitter	curation
Labcorp Genetics (formerly Invitae), Labcorp	RCV000056367	SCV002239663	pathogenic	Cystic fibrosis	2023-02-27	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 53508). This variant is also known as W846X1. This premature translational stop signal has been observed in individual(s) with cystic fibrosis (PMID: 7689897). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Trp846*) 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).
Baylor Genetics	RCV004566873	SCV005057447	pathogenic	Bronchiectasis with or without elevated sweat chloride 1	2024-01-16	criteria provided, single submitter	clinical testing
Counsyl	RCV000056367	SCV001132147	pathogenic	Cystic fibrosis	2015-08-05	no assertion criteria provided	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV001529697	SCV001743594	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001529697	SCV001970225	pathogenic	not provided		no assertion criteria provided	clinical testing
Natera, Inc.	RCV001826640	SCV002080761	pathogenic	CFTR-related disorder	2017-03-17	no assertion criteria provided	clinical testing