Submissions for variant NM_000492.4(CFTR):c.292C>T (p.Gln98Ter)

gnomAD frequency: 0.00001  dbSNP: rs397508461

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
CFTR2	RCV000056375	SCV000071549	pathogenic	Cystic fibrosis	2017-03-17	reviewed by expert panel	research
Counsyl	RCV000056375	SCV000220660	likely pathogenic	Cystic fibrosis	2014-08-29	criteria provided, single submitter	literature only
Mendelics	RCV000056375	SCV000886257	pathogenic	Cystic fibrosis	2018-11-05	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000781254	SCV000919163	pathogenic	not specified	2018-12-24	criteria provided, single submitter	clinical testing	Variant summary: CFTR c.292C>T (p.Gln98X) 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 1.1e-05 in 276762 control chromosomes (gnomAD). c.292C>T has been reported in the literature in multiple individuals affected with Cystic Fibrosis, including a report of homozygous occurrences (Sosnay_2013, Wong_2004, Malone_1998). These data indicate that the variant is very likely to be associated with disease. The variant is also reported in 17 patients in the reputable CFTR2 database where it is mentioned that it "causes CF when combined with another CF-causing variant" and it also "causes pancreatic insufficiency when combined with another variant that causes pancreatic insufficiency." Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae	RCV000056375	SCV002172936	pathogenic	Cystic fibrosis	2022-08-19	criteria provided, single submitter	clinical testing	ClinVar contains an entry for this variant (Variation ID: 53600). This premature translational stop signal has been observed in individual(s) with clinical features of cystic fibrosis (PMID: 9482579, 23974870). This variant is present in population databases (rs397508461, gnomAD 0.01%). This sequence change creates a premature translational stop signal (p.Gln98*) 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). 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.
Institute of Human Genetics, University of Leipzig Medical Center	RCV000056375	SCV002573946	pathogenic	Cystic fibrosis	2022-09-05	criteria provided, single submitter	curation	This variant was identified in 1 patient with a clinically confirmed diagnosis of cystic fibrosis. The variant was classified in the context of a project re-classifying variants in the German Cystic Fibrosis Registry (Muko.e.V.). Link: https://www.muko.info/angebote/qualitaetsmanagement/register/cf-einrichtungen/mukoweb. Criteria applied: PVS1, PM3_STR, PM2_SUP
Ambry Genetics	RCV000056375	SCV002748784	pathogenic	Cystic fibrosis	2023-04-18	criteria provided, single submitter	clinical testing	The p.Q98* pathogenic mutation (also known as c.292C>T), located in coding exon 4 of the CFTR gene, results from a C to T substitution at nucleotide position 292. This changes the amino acid from a glutamine to a stop codon within coding exon 4. This alteration has been reported in homozygous state in three Pakistani individuals with cystic fibrosis (Malone G et al. Hum. Mutat., 1998;11:152-7; Sosnay PR et al. Nat. Genet., 2013 Oct;45:1160-7). This variant has been reported in multiple individuals with an elevated sweat chloride level in The Clinical and Functional TRanslation of CFTR (CFTR2) database (available at http://cftr2.org. Accessed 04/18/2023). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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.
Baylor Genetics	RCV003474557	SCV004213506	pathogenic	Bronchiectasis with or without elevated sweat chloride 1	2023-05-15	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV001831761	SCV002080113	pathogenic	CFTR-related disorders	2017-03-17	no assertion criteria provided	clinical testing