rs75763344
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1PM2PM5PP3_StrongPP5
The NM_000492.4(CFTR):c.941G>A(p.Gly314Glu) variant causes a missense change. The variant allele was found at a frequency of 0.0000031 in 1,613,848 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G314A) has been classified as Uncertain significance.
Frequency
Consequence
NM_000492.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 11 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CFTR | NM_000492.4 | c.941G>A | p.Gly314Glu | missense_variant | 8/27 | ENST00000003084.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CFTR | ENST00000003084.11 | c.941G>A | p.Gly314Glu | missense_variant | 8/27 | 1 | NM_000492.4 | P2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152104Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251236Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135790
GnomAD4 exome AF: 0.00000205 AC: 3AN: 1461744Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1AN XY: 727172
GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152104Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74288
ClinVar
Submissions by phenotype
Cystic fibrosis Pathogenic:5Uncertain:2Other:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Jul 22, 2021 | - - |
not provided, no classification provided | literature only | ClinVar Staff, National Center for Biotechnology Information (NCBI) | - | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 24, 2017 | 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Apr 18, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Mendelics | Nov 05, 2018 | - - |
Likely pathogenic, criteria provided, single submitter | curation | Institute of Human Genetics, University of Leipzig Medical Center | Sep 05, 2022 | This variant was identified in 1 patient with a clinically confirmed diagnosis of cystic fibrosis. The variant was classified in the context of a project re-classifying variants in the German Cystic Fibrosis Registry (Muko.e.V.). Link: https://www.muko.info/angebote/qualitaetsmanagement/register/cf-einrichtungen/mukoweb. Criteria applied: PM2_SUP, PM3, PM5_STR, PP3, PP4 - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Johns Hopkins Genomics, Johns Hopkins University | Oct 13, 2023 | CFTR variant associated with varying clinical consequence. See www.CFTR2.org for phenotype information. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 09, 2023 | 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. - |
Cystic fibrosis;C0403814:Congenital bilateral aplasia of vas deferens from CFTR mutation Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | - | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Sep 01, 2019 | - - |
CFTR-related disorder Pathogenic:1
Likely pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Aug 28, 2018 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at