Submissions for variant NM_000492.4(CFTR):c.2989-2A>G

dbSNP: rs193922515

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
CFTR2	RCV000046741	SCV000245959	pathogenic	Cystic fibrosis	2017-03-17	reviewed by expert panel	research
Baylor Genetics	RCV001004286	SCV001163162	pathogenic	Cystic fibrosis; Congenital bilateral aplasia of vas deferens from CFTR mutation		criteria provided, single submitter	clinical testing
Johns Hopkins Genomics, Johns Hopkins University	RCV000046741	SCV001167239	pathogenic	Cystic fibrosis	2019-10-15	criteria provided, single submitter	clinical testing	Disease-causing CFTR variant. See www.CFTR2.org for phenotype information.
CFTR-France	RCV000046741	SCV001169550	pathogenic	Cystic fibrosis	2018-01-29	criteria provided, single submitter	curation
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000046741	SCV001337780	pathogenic	Cystic fibrosis	2020-01-16	criteria provided, single submitter	clinical testing	Variant summary: CFTR c.2989-2A>G is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a 3' acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 251074 control chromosomes. c.2989-2A>G has been reported in the literature in individuals affected with Cystic Fibrosis (eg. Reiss_1993, Hirtz_2004, Sapiejka_2018, Macek_1997). These data indicate that the variant is likely to be associated with disease. Functional studies have shown that native colonic epithelia containing the variant of interest had absent CFTR-mediated Cl- secretion (Hirtz_2004). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000046741	SCV001580394	pathogenic	Cystic fibrosis	2022-06-13	criteria provided, single submitter	clinical testing	Disruption of this splice site has been observed in individuals with cystic fibrosis (PMID: 7541510, 7689013, 9452048). This variant is not present in population databases (gnomAD no frequency). This sequence change affects an acceptor splice site in intron 18 of the CFTR gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in CFTR are known to be pathogenic (PMID: 1695717, 7691345, 9725922). ClinVar contains an entry for this variant (Variation ID: 53614). For these reasons, this variant has been classified as Pathogenic. Studies have shown that disruption of this splice site alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 23974870).
Institute of Human Genetics, University of Leipzig Medical Center	RCV000046741	SCV002574068	pathogenic	Cystic fibrosis	2022-09-05	criteria provided, single submitter	curation	This variant was identified in 14 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: PVS1, PM3_VSTR, PS1_SUP, PM2_SUP, PP4
Ambry Genetics	RCV000046741	SCV002751250	pathogenic	Cystic fibrosis	2018-08-31	criteria provided, single submitter	clinical testing	The c.2989-2A>G intronic pathogenic mutation (also known as 3121-2A>G) results from an A to G substitution two nucleotides upstream from coding exon 19 in the CFTR gene. This mutation was identified in a German cohort with cystic fibrosis (CF); however, complete genotype and phenotype information was not provided (Reiss J et al. Hum. Mol. Genet., 1993 Jun;2:809-11). In another study, this mutation was identified in the homozygous state in a Japanese female with CF and elevated sweat chloride levels (Macek M et al. Hum. Mutat., 1997;9:136-47). In addition to the clinical data presented in the literature, alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as a disease-causing mutation.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV003114231	SCV003799780	pathogenic	not provided	2022-03-04	criteria provided, single submitter	clinical testing	The CFTR c.2989-2A>G variant (rs193922515), also known as 3121-2G>A, is reported in the literature in multiple individuals affected with cystic fibrosis often found homozygous or in trans with a second pathogenic CFTR variant (Hirtz 2004, Macek 1997, Petrova 2020, Reiss 1993, Sapiejka 2018). This variant is reported as pathogenic by an expert panel in ClinVar (Variation ID: 53614) and is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. This variant disrupts the canonical splice donor site of intron 16, which is likely to negatively impact gene function. Based on available information, this variant is considered to be pathogenic. References: Hirtz S et al. CFTR Cl- channel function in native human colon correlates with the genotype and phenotype in cystic fibrosis. Gastroenterology. 2004 Oct;127(4):1085-95. PMID: 15480987. Macek M Jr et al. Sensitivity of the denaturing gradient gel electrophoresis technique in detection of known mutations and novel Asian mutations in the CFTR gene. Hum Mutat. 1997;9(2):136-47. PMID: 9067754. Petrova NV et al. Analysis of CFTR Mutation Spectrum in Ethnic Russian Cystic Fibrosis Patients. Genes (Basel). 2020 May 15;11(5):554. PMID: 32429104. Reiss J et al. A comprehensive CFTR mutation analysis of German cystic fibrosis patients. Hum Mol Genet. 1993 Jun;2(6):809-11. PMID: 7689013. Sapiejka E et al. Vitamin E status and its determinants in patients with cystic fibrosis. Adv Med Sci. 2018 Sep;63(2):341-346. PMID: 30081288.
Baylor Genetics	RCV003474562	SCV004213510	pathogenic	Bronchiectasis with or without elevated sweat chloride 1	2023-05-08	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV001831765	SCV002083574	pathogenic	CFTR-related disorder	2017-03-17	no assertion criteria provided	clinical testing