Submissions for variant NM_000492.4(CFTR):c.1923_1931delinsA (p.Ser641fs)

dbSNP: rs121908779

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
CFTR2	RCV000046508	SCV000245882	pathogenic	Cystic fibrosis	2017-03-17	reviewed by expert panel	research
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000780128	SCV000917172	pathogenic	not specified	2017-09-06	criteria provided, single submitter	clinical testing	Variant summary: The CFTR c.1923_1931delinsA (p.Ser641ArgfsX5) variant results in a premature termination codon, predicted to cause a truncated or absent CFTR 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 (e.g. c.1973_1985delinsAGAAA, p.Arg658fsX4; c.1976delA, p.Asn659fsX4; c.1986_1989delAACT, p.Thr663fsX8). One in silico tool predicts a damaging outcome for this variant. The variant was not found in the control population dataset of ExAC in 120642 control chromosomes. Multiple publications have cited the variant in homozygous and compound heterozygote individuals with CF (predominantly Hispanic)(Orozco_1997, Orozco_1997, Kammesheidt_2006). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Baylor Genetics	RCV001004279	SCV001163155	pathogenic	Cystic fibrosis; Congenital bilateral aplasia of vas deferens from CFTR mutation		criteria provided, single submitter	clinical testing
Johns Hopkins Genomics, Johns Hopkins University	RCV000046508	SCV001167247	pathogenic	Cystic fibrosis	2019-10-16	criteria provided, single submitter	clinical testing	Disease-causing CFTR variant. See www.CFTR2.org for phenotype information.
Myriad Genetics, Inc.	RCV000046508	SCV001194020	pathogenic	Cystic fibrosis	2019-12-09	criteria provided, single submitter	clinical testing	NM_000492.3(CFTR):c.1923_1931del9ins1(S641Rfs*5, aka 2055del9->A) is classified as pathogenic in the context of cystic fibrosis. Sources cited for classification include the following: PMID 9298826, 10798368 and 21416780. Classification of NM_000492.3(CFTR):c.1923_1931del9ins1(S641Rfs*5, aka 2055del9->A) is based on the following criteria: The variant causes a premature termination codon that is expected to be targeted by nonsense-mediated mRNA decay and is reported in individuals with the relevant phenotype. Please note: this variant was assessed in the context of healthy population screening.
Mayo Clinic Laboratories, Mayo Clinic	RCV001508587	SCV001714838	pathogenic	not provided	2020-03-16	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001508587	SCV003800027	pathogenic	not provided	2022-11-28	criteria provided, single submitter	clinical testing	The CFTR c.1923_1931delinsA; p.Ser641ArgfsTer5 variant (rs121908779), also known as 2055del9>A, is reported in the literature in two individuals affected with cystic fibrosis, one of whom was a compound heterozygote with another pathogenic variant (Orozco 1997). The CFTR2 database reports pancreatic insufficiency in 93% of individuals carrying the p.Ser641ArgfsTer5 variant with a second pathogenic CFTR variant (see link). This variant is also reported in ClinVar (Variation ID: 38735), but is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. This variant causes a frameshift by deleting nine nucleotides and inserting a single adenosine, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered to be pathogenic. References: CFTR2 database: https://cftr2.org Orozco L et al. Two novel frameshift deletions (1924del7, 2055del9-->A) in the CFTR gene in Mexican cystic fibrosis patients. Hum Mutat. 1997;10(3):239-40.
Baylor Genetics	RCV003473245	SCV004213448	pathogenic	Bronchiectasis with or without elevated sweat chloride 1	2024-01-22	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV001027891	SCV001190613	pathogenic	CFTR-related disorder	2019-05-20	no assertion criteria provided	clinical testing