Submissions for variant NM_000492.4(CFTR):c.3067_3072del (p.Ile1023_Val1024del)

dbSNP: rs121908767

Total submissions: 17

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
CFTR2	RCV000046775	SCV001981576	pathogenic	Cystic fibrosis	2021-09-24	reviewed by expert panel	research
Labcorp Genetics (formerly Invitae), Labcorp	RCV000046775	SCV000074788	pathogenic	Cystic fibrosis	2023-12-03	criteria provided, single submitter	clinical testing	This variant, c.3067_3072del, results in the deletion of 2 amino acid(s) of the CFTR protein (p.Ile1023_Val1024del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs397508492, gnomAD 0.01%). This variant has been observed in individual(s) with cystic fibrosis or congenital absence of the vas deferens (PMID: 7516234, 12394343, 15287992, 22020151, 22627569). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as 3199del6 or 3195del6. ClinVar contains an entry for this variant (Variation ID: 38480). For these reasons, this variant has been classified as Pathogenic.
Eurofins Ntd Llc (ga)	RCV000757083	SCV000331277	pathogenic	not provided	2012-08-06	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000046775	SCV000696944	pathogenic	Cystic fibrosis	2016-01-18	criteria provided, single submitter	clinical testing	Variant summary: The c.3067_3072delATAGTG (a.k.a. 3199del6) in CFTR gene is an in-frame deletion that expected to remove Ile1023 and Val1024 from the CFTR protein. Mutation Taster predicts deleterious outcome. The variant is absent from the large and broad cohorts of the ExAC project. The variant of interest has been identified in multiple affected individuals presented with CF and was referred as causative mutation in peer-reviewed publications. At least one reputable clinical laboratory/diagnostic center classified the variant as Pathogenic. Taking together, the variant was classified as Pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000757083	SCV000885187	pathogenic	not provided	2017-05-18	criteria provided, single submitter	clinical testing
Mendelics	RCV000046775	SCV000886159	likely pathogenic	Cystic fibrosis	2018-11-05	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV001004289	SCV001163165	pathogenic	Cystic fibrosis; Congenital bilateral aplasia of vas deferens from CFTR mutation		criteria provided, single submitter	clinical testing
CFTR-France	RCV000046775	SCV001169285	pathogenic	Cystic fibrosis	2018-01-29	criteria provided, single submitter	curation
Myriad Genetics, Inc.	RCV000046775	SCV001193959	pathogenic	Cystic fibrosis	2019-12-04	criteria provided, single submitter	clinical testing	NM_000492.3(CFTR):c.3067_3072del6(aka 3199del6) is classified as pathogenic in the context of cystic fibrosis. Sources cited for classification include the following: PMID 15371908, 10798368, 12172395, 15371907, 11668613, 8707304, 15371903, 15017334, 15638824, 7516234, 22020151, 18456578, 12394343 and 21679131. Classification of NM_000492.3(CFTR):c.3067_3072del6(aka 3199del6) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.
Johns Hopkins Genomics, Johns Hopkins University	RCV000046775	SCV001425301	pathogenic	Cystic fibrosis	2020-03-04	criteria provided, single submitter	clinical testing	c.3067_3072del has been observed in multiple patients presenting with cystic fibrosis in whom a second disease-associated variant was identified. This variant (rs397508492) is rare (<0.1%) in a large population dataset (gnomAD: 7/251080 total alleles; 0.002788%; no homozygotes). Additionally, seven submitters in ClinVar classify this variant as either pathogenic or likely pathogenic. We consider this variant to be pathogenic.
Institute of Human Genetics, University of Leipzig Medical Center	RCV000046775	SCV002574073	pathogenic	Cystic fibrosis	2022-09-05	criteria provided, single submitter	curation	This variant was identified in 4 unrelated patients 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: PM2_SUP, PM3_VSTR, PM4, PP4
Ambry Genetics	RCV000046775	SCV002753642	pathogenic	Cystic fibrosis	2023-01-11	criteria provided, single submitter	clinical testing	The c.3067_3072delATAGTG pathogenic mutation (also known as 3199del6, 3195del6, and p.I1023_V1024del) is located in coding exon 19 of the CFTR gene. This pathogenic mutation results from an in-frame deletion of 6 nucleotides at positions 3067 to 3072. This results in the deletion of an isoleucine and a valine residue between codons 1023 and 1024. This mutation was first reported in an individual with cystic fibrosis (CF) in trans with a frameshift alteration (Claustres M et al. Hum. Mol. Genet., 1994 Feb;3:371). In another study, this mutation was identified in trans with a nonsense alteration in an individual with CF with meconium ileus, pulmonary symptoms, pancreatic sufficiency, and elevated sweat chloride levels (Buyse IM et al. Genet. Med.;6:426-30). In a cohort of unrelated French Canadian individuals with CF, 21 of 22 individuals bearing this mutation and another severe CFTR alteration were pancreatic insufficient (Ruchon AF et al. Genet. Med., 2005 Mar;7:210-1). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Revvity Omics, Revvity	RCV000757083	SCV003820761	pathogenic	not provided	2023-01-13	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003473238	SCV004213270	pathogenic	Bronchiectasis with or without elevated sweat chloride 1	2024-03-11	criteria provided, single submitter	clinical testing
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV000757083	SCV005196953	pathogenic	not provided	2022-06-16	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV001826528	SCV002083586	pathogenic	CFTR-related disorder	2017-03-17	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV001826528	SCV005360563	pathogenic	CFTR-related disorder	2024-07-19	no assertion criteria provided	clinical testing	The CFTR c.3067_3072del6 variant is predicted to result in an in-frame deletion (p.Ile1023_Val1024del). This variant, also referred to as 3199del6 using legacy nomenclature, has been reported to be causative for cystic fibrosis (see, for example, Buyse et al. 2004. PubMed ID: 15371908; Monaghan et al. 2004. PubMed ID: 15371907; Castellani et al. 2008. PubMed ID: 18456578; Sosnay PR et al 2013. PubMed ID: 23974870; https://cftr2.org). This variant is reported in 0.017% of alleles in individuals of Latino descent in gnomAD and is interpreted as pathogenic by multiple laboratories in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/38480/). Based on the available evidence, we classify this variant as pathogenic.