Submissions for variant NM_000492.4(CFTR):c.2763_2764dup (p.Val922fs)

dbSNP: rs397508431

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
CFTR2	RCV000046684	SCV000245903	pathogenic	Cystic fibrosis	2017-03-17	reviewed by expert panel	research
CFTR-France	RCV000046684	SCV001169512	pathogenic	Cystic fibrosis	2018-01-29	criteria provided, single submitter	curation
Labcorp Genetics (formerly Invitae), Labcorp	RCV000046684	SCV001583430	pathogenic	Cystic fibrosis	2023-02-16	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 53563). This variant is also known as c.2896insAG. This premature translational stop signal has been observed in individual(s) with congenital absence of vas deferens (PMID: 10200050). This variant is present in population databases (rs397508431, gnomAD 0.0009%). This sequence change creates a premature translational stop signal (p.Val922Glufs*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).
Ambry Genetics	RCV000046684	SCV002747155	pathogenic	Cystic fibrosis	2014-12-22	criteria provided, single submitter	clinical testing	The c.2763_2764dupAG pathogenic mutation located in coding exon 17 of the CFTR gene, results from duplication of the nucletides AG at position 2763, causing a translational frameshift with a predicted alternate stop codon. One study lists this mutation in a patient with CBAVD with another CFTR mutation in trans (de Meeus et al 1998; Hum Mutat 11(6):480). In addition to literature, since frameshifts are typically deleterious in nature, this alteration is interpreted as a disease-causing mutation (ACMG Recommendations for Standards for Interpretation and Reporting of Sequence Variations. Revision 2007. Genet Med. 2008;10:294). This mutation is also listed as 2896insAG in the literature.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000046684	SCV002766056	pathogenic	Cystic fibrosis	2022-11-28	criteria provided, single submitter	clinical testing	Variant summary: CFTR c.2763_2764dupAG (p.Val922GlufsX2), also referred to as c.2896insAG, 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 allele was found at a frequency of 4e-06 in 251410 control chromosomes (gnomAD). c.2763_2764dupAG has been reported in the literature in the compound heterozygous state in individuals affected with Congenital Bilateral Absense of the Vas Deferens (CBAVD) and in individuals affected with Cystic Fibrosis (e.g. de Meeus_1997, Clausters_2000, Munck_2020, Walton_2021). These data indicate that the variant is likely to be associated with disease. Four submitters, including the expert panel CFTR2, have provided clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics	RCV003474552	SCV004213463	pathogenic	Bronchiectasis with or without elevated sweat chloride 1	2023-07-13	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV001831756	SCV002080802	pathogenic	CFTR-related disorder	2018-09-05	no assertion criteria provided	clinical testing