Submissions for variant NM_000492.4(CFTR):c.1973_1985delinsAGAAA

dbSNP: rs121908780

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
CFTR2	RCV000046511	SCV000245883	pathogenic	Cystic fibrosis	2017-03-17	reviewed by expert panel	research
Labcorp Genetics (formerly Invitae), Labcorp	RCV000046511	SCV000751419	pathogenic	Cystic fibrosis	2024-06-08	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg658Lysfs*4) 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 cystic fibrosis and/or other CFTR-related conditions (PMID: 11668613, 18456578, 26708955). This variant is also known as 2105-2117del13insAGAAA. For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics	RCV001004280	SCV001163156	pathogenic	Cystic fibrosis; Congenital bilateral aplasia of vas deferens from CFTR mutation		criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000046511	SCV001363803	pathogenic	Cystic fibrosis	2020-08-25	criteria provided, single submitter	clinical testing	Variant summary: CFTR c.1973_1985delinsAGAAA (p.Arg658LysfsX4) 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. The variant was absent in 250848 control chromosomes. c.1973_1985delinsAGAAA has been reported in the literature in multiple individuals affected with Cystic Fibrosis (examples- Wong_2000, 2001, Shrijver_2005, Kay_2015). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories cited the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001284133	SCV001469757	pathogenic	not provided	2019-10-18	criteria provided, single submitter	clinical testing	The variant results in a shift of the reading frame, and is therefore predicted to result in the loss of a functional protein. Found in at least one patient with expected phenotype for this gene, and not found in general population data.
Mayo Clinic Laboratories, Mayo Clinic	RCV001284133	SCV001714839	pathogenic	not provided	2020-04-27	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000046511	SCV002723445	pathogenic	Cystic fibrosis	2024-05-30	criteria provided, single submitter	clinical testing	The c.1973_1985del13insAGAAA pathogenic mutation, located in coding exon 14 of the CFTR gene, results from the deletion of 13 nucleotides and insertion of 5 nucleotides causing a translational frameshift with a predicted alternate stop codon (p.R658Kfs*4). This mutation was detected in trans with p.F508del in two Hispanic siblings with cystic fibrosis (CF) (Wong LJ et al. Prenat. Diagn., 2000 Oct;20:807-10). This mutation has been reported as one of the most frequent CFTR alterations in Hispanic individuals with CF in the United States (Schrijver I et al. J Mol Diagn, 2016 Jan;18:39-50). 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.
PreventionGenetics, part of Exact Sciences	RCV004528258	SCV004112301	pathogenic	CFTR-related disorder	2023-05-16	criteria provided, single submitter	clinical testing	The CFTR c.1973_1985delinsAGAAA variant is predicted to result in a frameshift and premature protein termination (p.Arg658Lysfs*4). This variant, also referred to as 2105-2117 del13insAGAAA, has been reported in multiple individuals with cystic fibrosis and other CFTR-related disorders (Wong et al. 2000. PubMed ID: 11038458; Schrijver et al. 2005. PubMed ID: 15858154; Prach et al. 2013. PubMed ID: 23810505; cftr2.org). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Frameshift variants in CFTR are expected to be pathogenic. This variant is interpreted as pathogenic.
Baylor Genetics	RCV003473471	SCV004213342	pathogenic	Bronchiectasis with or without elevated sweat chloride 1	2024-03-30	criteria provided, single submitter	clinical testing
Johns Hopkins Genomics, Johns Hopkins University	RCV000046511	SCV004239041	pathogenic	Cystic fibrosis	2023-12-01	criteria provided, single submitter	clinical testing	Disease-causing CFTR variant. See www.CFTR2.org for phenotype information.