Submissions for variant NM_000492.4(CFTR):c.1340del (p.Lys447fs)

dbSNP: rs397508192

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
CFTR2	RCV000046278	SCV000245888	pathogenic	Cystic fibrosis	2017-03-17	reviewed by expert panel	research
Counsyl	RCV000046278	SCV000486001	pathogenic	Cystic fibrosis	2016-03-14	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000046278	SCV000696835	pathogenic	Cystic fibrosis	2016-01-18	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001001369	SCV001158567	pathogenic	not specified	2019-06-19	criteria provided, single submitter	clinical testing	The CFTR c.1340delA; p.Lys447fs variant (rs397508192) is reported in the literature in multiple individuals affected with cystic fibrosis (Mott 2009, CFTR2 database). At least one affected individual with this variant was observed to carry a second pathogenic CFTR variant (Mott 2009). This variant is found on a single chromosome (1/242968 alleles) in the Genome Aggregation Database, indicating it is not a common polymorphism. This variant causes a frameshift by deleting a single nucleotide, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered to be pathogenic. References: CFTR2 database: https://cftr2.org Mott LS et al. Bronchiectasis in an asymptomatic infant with cystic fibrosis diagnosed following newborn screening. J Cyst Fibros. 2009 Jul;8(4):285-7.
Baylor Genetics	RCV001004445	SCV001163490	pathogenic	Cystic fibrosis; Congenital bilateral aplasia of vas deferens from CFTR mutation		criteria provided, single submitter	clinical testing
Johns Hopkins Genomics, Johns Hopkins University	RCV000046278	SCV001433655	pathogenic	Cystic fibrosis	2019-12-17	criteria provided, single submitter	clinical testing	Previously reported disease-causing CFTR variant. See www.CFTR2.org for phenotype information.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000046278	SCV001579494	pathogenic	Cystic fibrosis	2024-09-17	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Lys447Argfs*2) 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). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individual(s) with cystic fibrosis (PMID: 19447078, 23974870, 26574590). ClinVar contains an entry for this variant (Variation ID: 53233). 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.
Ambry Genetics	RCV000046278	SCV002693649	pathogenic	Cystic fibrosis	2022-02-04	criteria provided, single submitter	clinical testing	The c.1340delA pathogenic mutation, located in coding exon 10 of the CFTR gene, results from a deletion of one nucleotide at nucleotide position 1340, causing a translational frameshift with a predicted alternate stop codon (p.K447Rfs*2). This alteration has been identified in multiple individuals with cystic fibrosis with a second CFTR variant (Andrew et al. Cystic Fibrosis Mutation Database [database online] Toronto, ON, Canada: SickKids;1999; Mott LS et al. J Cyst Fibros, 2009 Jul;8:285-7). In another study, this mutation was identified in 2 affected individuals in a cohort study of Celtic origin. Individuals in the cohort had a sweat chloride test result above 60 mmol/L and/or Pseudomonas colonization of the lungs (Scotet V et al. Human Mutat. 2003;22(1):105). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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	RCV003473450	SCV004213315	pathogenic	Bronchiectasis with or without elevated sweat chloride 1	2023-10-12	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV001835653	SCV002080578	pathogenic	CFTR-related disorder	2017-03-17	no assertion criteria provided	clinical testing