Submissions for variant NM_000492.4(CFTR):c.2797A>G (p.Arg933Gly)

gnomAD frequency: 0.00001  dbSNP: rs397508436

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000595350	SCV000709044	uncertain significance	not provided	2017-06-08	criteria provided, single submitter	clinical testing
CFTR-France	RCV001009477	SCV001169572	pathogenic	CFTR-related disorder	2018-01-29	criteria provided, single submitter	curation
Genome-Nilou Lab	RCV000577327	SCV001822124	uncertain significance	Cystic fibrosis	2021-07-22	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV001588877	SCV001822125	likely pathogenic	Congenital bilateral aplasia of vas deferens from CFTR mutation	2021-07-22	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000577327	SCV002500682	likely pathogenic	Cystic fibrosis	2024-12-26	criteria provided, single submitter	clinical testing	Variant summary: CFTR c.2797A>G (p.Arg933Gly) results in a non-conservative amino acid change located in the transmembrane domain (IPR011527) of the encoded protein sequence. Four of four in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251410 control chromosomes. c.2797A>G has been reported in the literature in the compound heterozygous and heterozygous states in individuals affected with CFTR-Related Diseases (Nick_2010, Sermet-Gaudelus_2010, Munck_2020, Fang_2022, Wang_2024). These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect resulted in approximately 14% of normal chloride channel conductance relative to wild type (e.g., Bihler_2024). The following publications have been ascertained in the context of this evaluation (PMID: 18687795, 38388235, 20059485, 36437957, 33922413, 22573477, 31916691, 20448091, 25735457, 34583889, 31674704, 20522854, 38114870, 26277102). ClinVar contains an entry for this variant (Variation ID: 53569). Based on the evidence outlined above, the variant was classified as likely pathogenic.
Ambry Genetics	RCV000577327	SCV002748328	uncertain significance	Cystic fibrosis	2022-10-11	criteria provided, single submitter	clinical testing	The p.R933G variant (also known as c.2797A>G), located in coding exon 17 of the CFTR gene, results from an A to G substitution at nucleotide position 2797. The arginine at codon 933 is replaced by glycine, an amino acid with dissimilar properties. This variant was identified in an infant with hypertrypsinaemia in conjunction with p.F508del; this individual had a nasal potential difference similar to individuals with cystic fibrosis (CF), but no chronic pulmonary disease, CF pathogens, airway obstruction, or pancreatic insufficiency at age 4 years (Sermet-Gaudelus I et al. Thorax, 2010 Jun;65:539-44). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on available evidence to date, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000577327	SCV003281200	likely pathogenic	Cystic fibrosis	2024-12-10	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 933 of the CFTR protein (p.Arg933Gly). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of CFTR-related conditions (PMID: 20448091, 20522854, 26277102; internal data). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 53569). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt CFTR protein function with a positive predictive value of 80%. This variant disrupts the p.Arg933 amino acid residue in CFTR. Other variant(s) that disrupt this residue have been observed in individuals with CFTR-related conditions (PMID: 9272157, 20448091; internal data), which suggests that this may be a clinically significant amino acid residue. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Johns Hopkins Genomics, Johns Hopkins University	RCV000577327	SCV003927240	likely pathogenic	Cystic fibrosis	2023-03-10	criteria provided, single submitter	clinical testing	CFTR variant associated with varying clinical consequence. See www.CFTR2.org for phenotype information.
ClinVar Staff, National Center for Biotechnology Information (NCBI)	RCV000577327	SCV000679022	not provided	Cystic fibrosis		no assertion provided	literature only