Submissions for variant NM_000492.4(CFTR):c.850dup (p.Met284fs)

dbSNP: rs786204693

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
CFTR2	RCV000169503	SCV000924251	pathogenic	Cystic fibrosis	2017-12-08	reviewed by expert panel	research
Counsyl	RCV000169503	SCV000220966	likely pathogenic	Cystic fibrosis	2014-12-18	criteria provided, single submitter	literature only
Eurofins Ntd Llc (ga)	RCV000790771	SCV000340673	pathogenic	not provided	2016-03-28	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000169503	SCV001362620	pathogenic	Cystic fibrosis	2022-04-12	criteria provided, single submitter	clinical testing	Variant summary: The variant, CFTR c.850dupA (p.Met284AsnfsX3, also known as legacy name 977insA) 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 (eg. c.861_865delCTTAA (p.Met284fsX3), c.948delT (p.Phe316fsX12)). The variant was absent in 244174 control chromosomes (gnomAD) and has been reported in the literature in individuals affected with Cystic Fibrosis (Cheadle_1993, Schwarz_1995). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three 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.
Ambry Genetics	RCV000169503	SCV002675437	pathogenic	Cystic fibrosis	2014-09-12	criteria provided, single submitter	clinical testing	The c.850dupA pathogenic mutation (also known as 977insA), located in coding exon 7 of the CFTR gene, results from a duplication of A at nucleotide position 850, causing a translational frameshift with a predicted alternate stop codon (p.M284Nfs*3). This pathogenic mutation was first reported in an individual with mild to moderate lung disease who was pancreatic sufficient; this individual also carried the deltaF508 pathogenic mutation (Cheadle JP et al. Hum Mol Genet. 1993; 2(3):317-9). In addition to the clinical data presented in the 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).
Labcorp Genetics (formerly Invitae), Labcorp	RCV000169503	SCV003440100	pathogenic	Cystic fibrosis	2023-11-06	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Met284Asnfs*3) 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 clinical features of cystic fibrosis (PMID: 7684644). 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 c.977insA. ClinVar contains an entry for this variant (Variation ID: 189095). For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics	RCV004567369	SCV005057482	pathogenic	Bronchiectasis with or without elevated sweat chloride 1	2023-11-08	criteria provided, single submitter	clinical testing
Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital	RCV000169503	SCV005420801	pathogenic	Cystic fibrosis	2024-10-04	criteria provided, single submitter	research	PVS1,PM2,PP4
Natera, Inc.	RCV001027912	SCV001190635	pathogenic	CFTR-related disorder	2019-05-20	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV001027912	SCV005342568	pathogenic	CFTR-related disorder	2024-03-13	no assertion criteria provided	clinical testing	The CFTR c.850dupA variant is predicted to result in a frameshift and premature protein termination (p.Met284Asnfs*3). This variant, also described as c.844_845insA, c.845_846insA, and 977insA, has been reported in multiple individuals with cystic fibrosis, including at least eight individuals in the CFTR2 database (Cheadle et al. 1993. PubMed ID: 7684644; Trujillano et al. 2015. PubMed ID: 26436105; Park et al. 2020. PubMed ID: 33014932; https://cftr2.org/mutation/general/977insA/). In vitro functional studies on cultured nasal epithelial cells from a patient heterozygous for both p.Met284Asnfs*3 and p.Phe508del showed these cells retained only ~12% residual CFTR activity compared to control (Park et al. 2020. PubMed ID: 33014932). This variant has not been reported in a large population database, indicating this variant is rare. Frameshift variants in CFTR are expected to be pathogenic. This variant is interpreted as pathogenic.