Submissions for variant NM_000492.4(CFTR):c.3747del (p.Lys1250fs)

dbSNP: rs797045159

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
CFTR2	RCV000191001	SCV000245948	pathogenic	Cystic fibrosis	2017-03-17	reviewed by expert panel	research
Labcorp Genetics (formerly Invitae), Labcorp	RCV000191001	SCV002143588	pathogenic	Cystic fibrosis	2024-12-23	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Lys1250Argfs*9) 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 CFTR-related conditions (PMID: 12120234). This variant is also known as 3878delG, 3876delA, and 3744delA. ClinVar contains an entry for this variant (Variation ID: 209056). For these reasons, this variant has been classified as Pathogenic.
Mendelics	RCV002247617	SCV002518688	pathogenic	Hereditary pancreatitis	2022-05-04	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000191001	SCV002621965	pathogenic	Cystic fibrosis	2018-11-13	criteria provided, single submitter	clinical testing	The c.3747delG pathogenic mutation (also known as 3878delG), located in coding exon 23 of the CFTR gene, results from a deletion of one nucleotide at nucleotide position 3747, causing a translational frameshift with a predicted alternate stop codon (p.K1250Rfs*9). This mutation was reported in one individual with pancreatitis in conjunction with a second CFTR alteration; however, the phase was not provided (Castellani C et al. Hum. Mutat., 2001 Aug;18:166; Gomez Lira M et al. Pancreatology, 2001;1:538-42). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000191001	SCV004028749	pathogenic	Cystic fibrosis	2023-07-26	criteria provided, single submitter	clinical testing	Variant summary: CFTR c.3747delG (p.Lys1250ArgfsX9) 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 was absent in 251006 control chromosomes (gnomAD). c.3747delG has been reported in the literature in individuals affected with Cystic Fibrosis (e.g., Terlizzi_2018). These data indicate that the variant is very likely to be associated with disease. The following publication was ascertained in the context of this evaluation (PMID: 30577776). Five submitters have reported clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Natera, Inc.	RCV001833134	SCV002075878	pathogenic	CFTR-related disorder	2017-03-17	no assertion criteria provided	clinical testing