Submissions for variant NM_000492.4(CFTR):c.4297G>T (p.Glu1433Ter)

dbSNP: rs750559671

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000674872	SCV000800276	likely pathogenic	Cystic fibrosis	2018-05-29	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV001004309	SCV001163186	likely pathogenic	Cystic fibrosis; Congenital bilateral aplasia of vas deferens from CFTR mutation		criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000674872	SCV002933486	pathogenic	Cystic fibrosis	2022-07-21	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Glu1433*) in the CFTR gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 48 amino acid(s) of the CFTR protein. For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the CFTR protein in which other variant(s) (p.Gln1476*) have been determined to be pathogenic (PMID: 11938439, 22020151, 25910067, 28544683, 30444886). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 558578). This variant has not been reported in the literature in individuals affected with CFTR-related conditions. This variant is not present in population databases (gnomAD no frequency).
Baylor Genetics	RCV003472175	SCV004213492	likely pathogenic	Bronchiectasis with or without elevated sweat chloride 1	2023-06-10	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000674872	SCV004803359	pathogenic	Cystic fibrosis	2024-01-15	criteria provided, single submitter	clinical testing	Variant summary: CFTR c.4297G>T (p.Glu1433X) results in a premature termination codon and although it is not predicted to result in nonsense mediated decay, it is expected to cause a truncation of the encoded protein, which is a commonly known mechanism for disease. Variants downstream of this position have been classified as pathogenic by our laboratory and others in ClinVar. The variant was absent in 250854 control chromosomes (gnomAD). c.4297G>T has been reported in the literature as a compound heterozygous genotype in at least one individual who was affected with CBAVD (e.g. Qu_2023). These data suggest the variant is likely to be associated with Cystic Fibrosis/CFTR-related disorders. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 36604502). ClinVar contains an entry for this variant (Variation ID: 558578). Based on the evidence outlined above, the variant was classified as pathogenic.