Submissions for variant NM_000492.4(CFTR):c.941G>A (p.Gly314Glu)

gnomAD frequency: 0.00001  dbSNP: rs75763344

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Mendelics	RCV000577297	SCV000886348	pathogenic	Cystic fibrosis	2018-11-05	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV001004243	SCV001163119	likely pathogenic	Cystic fibrosis; Congenital bilateral aplasia of vas deferens from CFTR mutation		criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV001093485	SCV001250503	pathogenic	not provided	2019-09-01	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000577297	SCV001577168	likely pathogenic	Cystic fibrosis	2024-03-13	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 314 of the CFTR protein (p.Gly314Glu). This variant is present in population databases (rs75763344, gnomAD 0.0009%). This missense change has been observed in individual(s) with clinical features of cystic fibrosis (PMID: 7509684, 18178635). 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: 54089). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on CFTR protein function. Experimental studies have shown that this missense change affects CFTR function (PMID: 9512029). This variant disrupts the p.Gly314 amino acid residue in CFTR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 8829633, 24586523). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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.
Genome-Nilou Lab	RCV000577297	SCV001822027	likely pathogenic	Cystic fibrosis	2021-07-22	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Leipzig Medical Center	RCV000577297	SCV002573896	likely pathogenic	Cystic fibrosis	2024-06-25	criteria provided, single submitter	clinical testing	Criteria applied: PM2,PM3,PM5,PS3_SUP,PP3
Ambry Genetics	RCV000577297	SCV002685020	uncertain significance	Cystic fibrosis	2017-01-24	criteria provided, single submitter	clinical testing	The p.G314E variant (also known as c.941G>A), located in coding exon 8 of the CFTR gene, results from a G to A substitution at nucleotide position 941. The glycine at codon 314 is replaced by glutamic acid, an amino acid with similar properties. This alteration was first reported in a 7 year old female presenting with acute pneumonia and a history of recurrent bronchitis; she was diagnosed with cystic fibrosis (CF) based on elevated sweat chloride levels and p.F508del was confirmed in trans. However, the entire CFTR gene was not analyzed in this individual, and the presence of an undetected mutation cannot be ruled out (Golla A et al. Hum. Mutat., 1994;3:67-8). A 15 year old patient with a history of bronchitis was determined to be homozygous for p.G314E. Her initial CF diagnosis was retracted following a normal clinical exam, including: no history of meconium ileus, normal sweat chloride levels, pancreatic sufficiency, and absence of Pseudomonas aeruginosa infection. In addition, this individual had a normal nasal potential difference and intestinal current measurements on rectal suction biopsy were normal (Stanke F et al. J. Med. Genet., 2008 Jan;45:47-54). In one functional study, p.G314E did not affect permeability selectivity, however the data suggest that this residue is important for the structural integrity of an anion binding site in the pore (Mansoura MK et al. Biophys. J., 1998 Mar;74:1320-32). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is conflicting at this time, the clinical significance of this alteration remains unclear.
Johns Hopkins Genomics, Johns Hopkins University	RCV000577297	SCV004239061	likely pathogenic	Cystic fibrosis	2023-10-13	criteria provided, single submitter	clinical testing	CFTR variant associated with varying clinical consequence. See www.CFTR2.org for phenotype information.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000577297	SCV005395666	likely pathogenic	Cystic fibrosis	2024-09-05	criteria provided, single submitter	clinical testing	Variant summary: CFTR c.941G>A (p.Gly314Glu) results in a non-conservative amino acid change located in the ABC transporter type 1, transmembrane domain (IPR011527) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251236 control chromosomes. c.941G>A has been reported in the literature in the homozygous and compound heterozygous state in individuals affected with mild Cystic Fibrosis (Stanke_2008, Golla_1993, Minso_2020, Nasr_1996, Castaldo_1996). These data indicate that the variant is likely to be associated with disease. Experimental studies evaluating protein function in vitro show that this variant results in decreased chloride channel conductance. The most pronounced variant effect resulted in approximately 27% of normal chloride channel conductance relative to wild type (e.g., Bihler_2024, Nasr_1996). This variant is also known as 1073G>A. The following publications have been ascertained in the context of this evaluation (PMID: 38388235, 8782047, 7509684, 33020115, 8829633, 18178635).ClinVar contains an entry for this variant (Variation ID: 54089). Based on the evidence outlined above, the variant was classified as likely pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV005031531	SCV005673303	likely pathogenic	Bronchiectasis with or without elevated sweat chloride 1; Cystic fibrosis; Hereditary pancreatitis; Congenital bilateral aplasia of vas deferens from CFTR mutation	2024-01-09	criteria provided, single submitter	clinical testing
ClinVar Staff, National Center for Biotechnology Information (NCBI)	RCV000577297	SCV000679191	not provided	Cystic fibrosis		no assertion provided	literature only
Counsyl	RCV000577297	SCV000791000	uncertain significance	Cystic fibrosis	2017-04-18	no assertion criteria provided	clinical testing	This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact [e-mail].
Natera, Inc.	RCV001826703	SCV002078159	likely pathogenic	CFTR-related disorder	2018-08-28	no assertion criteria provided	clinical testing