Submissions for variant NM_000492.4(CFTR):c.579+5G>A

gnomAD frequency: 0.00001  dbSNP: rs78440224

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
CFTR2	RCV000056397	SCV000071575	pathogenic	Cystic fibrosis	2017-03-17	reviewed by expert panel	research
Mendelics	RCV000056397	SCV000886200	pathogenic	Cystic fibrosis	2018-11-05	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV001004439	SCV001163484	pathogenic	Cystic fibrosis; Congenital bilateral aplasia of vas deferens from CFTR mutation		criteria provided, single submitter	clinical testing
CFTR-France	RCV000056397	SCV001169305	pathogenic	Cystic fibrosis	2018-01-29	criteria provided, single submitter	curation
Myriad Genetics, Inc.	RCV000056397	SCV001193796	pathogenic	Cystic fibrosis	2019-12-07	criteria provided, single submitter	clinical testing	NM_000492.3(CFTR):c.579+5G>A(aka 711+5G>A) is classified as pathogenic in the context of cystic fibrosis. Sources cited for classification include the following: PMID 23974870. Classification of NM_000492.3(CFTR):c.579+5G>A(aka 711+5G>A) 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000056397	SCV002170948	pathogenic	Cystic fibrosis	2023-10-20	criteria provided, single submitter	clinical testing	This sequence change falls in intron 5 of the CFTR gene. It does not directly change the encoded amino acid sequence of the CFTR protein. RNA analysis indicates that this variant induces altered splicing and likely results in a shortened protein product. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individuals with cystic fibrosis (PMID: 21779199, 23974870, 25553309, 30811104). This variant is also known as 711+5G>A. ClinVar contains an entry for this variant (Variation ID: 54012). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in skipping of exon 5, but is expected to preserve the integrity of the reading-frame (PMID: 32935393). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000056397	SCV002500259	pathogenic	Cystic fibrosis	2022-03-09	criteria provided, single submitter	clinical testing	Variant summary: CFTR c.579+5G>A alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a 5' splicing donor site. These predictions have been confirmed by experimental evidence showing the variant results in induced severe exon 5 skipping (Donega_2020). The variant was absent in 249772 control chromosomes. c.579+5G>A has been reported in the literature in numerous individuals affected with Cystic Fibrosis (e.g. Sosnay_2013). Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Institute of Human Genetics, University of Leipzig Medical Center	RCV000056397	SCV002573887	pathogenic	Cystic fibrosis	2022-09-05	criteria provided, single submitter	curation	This variant was identified in 1 patient 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: PS1_SUP, PS3_SUP, PM2_SUP, PM3_VSTR, PM4_STR, PP3, PP4
Ambry Genetics	RCV000056397	SCV002648946	pathogenic	Cystic fibrosis	2015-11-17	criteria provided, single submitter	clinical testing	The c.579+5G>A intronic variant (also known as c.711+5G>A) results from a G to A substitution 5 nucleotides after coding exon 5 in the CFTR gene. This variant was reported in 6 out of 225 CF chromosomes in an Italian cohort of individuals with classic disease and not in any normal chromosomes. However, the number of normal chromosomes was not disclosed (Bisceglia L et al. Hum Mutat. 1994;4(2):136-140). This mutation is associated with elevated sweat chloride levels, lung disease, and pancreatic insufficiency; an in vitro functional study showed this mutation resulted in significantly reduced mean chloride conductance (Sosnay PR et al. Nat Genet. 2013;45(10):1160-7, Supplementary Table and The Clinical and Functional Translation of CFTR (CFTR2); available at http://cftr2.org. Accessed March 16, 2015). Based on the supporting evidence, c.579+5G>A is interpreted as a disease-causing mutation.
Baylor Genetics	RCV003474610	SCV004213407	pathogenic	Bronchiectasis with or without elevated sweat chloride 1	2023-09-03	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV001831796	SCV002078112	pathogenic	CFTR-related disorder	2017-03-17	no assertion criteria provided	clinical testing