chr7-117509038-T-G
Position:
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PP3_StrongPP5_Very_Strong
The NM_000492.4(CFTR):c.169T>G(p.Trp57Gly) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★★).
Frequency
Genomes: not found (cov: 33)
Consequence
CFTR
NM_000492.4 missense
NM_000492.4 missense
Scores
9
7
3
Clinical Significance
Conservation
PhyloP100: 6.21
Genes affected
CFTR (HGNC:1884): (CF transmembrane conductance regulator) This gene encodes a member of the ATP-binding cassette (ABC) transporter superfamily. The encoded protein functions as a chloride channel, making it unique among members of this protein family, and controls ion and water secretion and absorption in epithelial tissues. Channel activation is mediated by cycles of regulatory domain phosphorylation, ATP-binding by the nucleotide-binding domains, and ATP hydrolysis. Mutations in this gene cause cystic fibrosis, the most common lethal genetic disorder in populations of Northern European descent. The most frequently occurring mutation in cystic fibrosis, DeltaF508, results in impaired folding and trafficking of the encoded protein. Multiple pseudogenes have been identified in the human genome. [provided by RefSeq, Aug 2017]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 16 ACMG points.
PM1
In a helix (size 17) in uniprot entity CFTR_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) in NM_000492.4
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.979
PP5
Variant 7-117509038-T-G is Pathogenic according to our data. Variant chr7-117509038-T-G is described in ClinVar as [Pathogenic]. Clinvar id is 53347.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr7-117509038-T-G is described in Lovd as [Pathogenic].
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| CFTR | NM_000492.4 | c.169T>G | p.Trp57Gly | missense_variant | 3/27 | ENST00000003084.11 | NP_000483.3 |
Ensembl
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
33
GnomAD4 exome Cov.: 28
GnomAD4 exome
Cov.:
28
GnomAD4 genome
GnomAD4 genome
Cov.:
33
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:9Other:1
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
Cystic fibrosis Pathogenic:6Other:1
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Mar 05, 2024 | This sequence change replaces tryptophan, which is neutral and slightly polar, with glycine, which is neutral and non-polar, at codon 57 of the CFTR protein (p.Trp57Gly). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with cystic fibrosis (PMID: 7544319, 23974870). ClinVar contains an entry for this variant (Variation ID: 53347). 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) performed at Invitae indicates that this missense variant is expected to disrupt CFTR protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects CFTR function (PMID: 29805046). This variant disrupts the p.Trp57 amino acid residue in CFTR. Other variant(s) that disrupt this residue have been observed in individuals with CFTR-related conditions (Invitae), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. - |
| Pathogenic, reviewed by expert panel | research | CFTR2 | Dec 08, 2017 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Oct 02, 2024 | Variant summary: CFTR c.169T>G (p.Trp57Gly) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250754 control chromosomes. c.169T>G has been reported in the literature in multiple individuals affected with Cystic Fibrosis (e.g. McCague_2019, Brancolini_1995). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in 0.75% of normal activity. The following publications have been ascertained in the context of this evaluation (PMID: 38388235, 7544319, 30888834). ClinVar contains an entry for this variant (Variation ID: 53347). Based on the evidence outlined above, the variant was classified as pathogenic. - |
| not provided, no classification provided | literature only | ClinVar Staff, National Center for Biotechnology Information (NCBI) | - | - - |
| Pathogenic, criteria provided, single submitter | curation | CFTR-France | Mar 26, 2020 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Mendelics | Nov 05, 2018 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | May 09, 2018 | The p.W57G pathogenic mutation (also known as c.169T>G), located in coding exon 3 of the CFTR gene, results from a T to G substitution at nucleotide position 169. The tryptophan at codon 57 is replaced by glycine, an amino acid with highly dissimilar properties. This mutation (referred to as 301T>G) was described in a patient with cystic fibrosis (CF) who had a second pathogenic mutation on the other allele (Brancolini V et al. Hum. Genet., 1995 Sep;96:312-8). It was also reportedly detected on two CF alleles in a Czech cohort (Kenková P et al. J. Cyst. Fibros., 2013 Sep;12:532-7). This amino acid position is highly conserved in available vertebrate species. Based on internal structural analysis, this mutation is more disruptive than known pathogenic variants nearby (Liu F et al. Cell, 2017 Mar;169:85-95.e8). In addition, in vitro studies showed that this tryptophan residue is essential for processing of the CFTR protein and W57G has almost no CFTR function (Cormet-Boyaka E et al. Proc. Natl. Acad. Sci. U.S.A., 2004 May;101:8221-6; The Clinical and Functional TRanslation of CFTR (CFTR2); available at http://cftr2.org. Accessed <May 9, 2018>). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. - |
CFTR-related disorder Pathogenic:1
| Pathogenic, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Jan 26, 2024 | The CFTR c.169T>G variant is predicted to result in the amino acid substitution p.Trp57Gly. This variant has been reported in the compound heterozygous state in multiple individuals with cystic fibrosis (Table 2, Brancolini et al. 1995. PubMed ID: 7544319; Table 1, Křenková et al. 2013. PubMed ID: 23276700; Table S4, Raraigh et al. 2022. PubMed ID: 34782259; CFTR2 database, cftr2.org; CFTR-France database, https://cftr.iurc.montp.inserm.fr/cftr). Multiple in vitro studies have demonstrated that this variant disrupts CFTR protein processing and trafficking to the cell membrane, leading to a complete loss of chloride channel function (Raraigh et al. 2018. PubMed ID: 29805046; Sabusap et al. 2021. PubMed ID: 33781744; Ramalho et al. 2022. PubMed ID: 35008443). This variant has not been reported in a large population database, indicating this variant is rare. A different missense variant at the same amino acid (p.Trp57Arg) has also been reported in individuals with cystic fibrosis (Table 1, Kinnunen et al. 2005. PubMed ID: 16051530; Table 2, De Wachter et al. 2017. PubMed ID: 28830496; Table 1, Auzenbaha et al. 2022. PubMed ID: 36428953). Taken together, the p.Trp57Gly variant is interpreted as pathogenic. - |
not provided Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Sep 01, 2022 | The CFTR c.169T>G; p.Trp57Gly variant (rs397508272) is reported in the literature in several individuals affected with cystic fibrosis (Brancolini 1995; Raraigh 2018). Functional analyses of the variant protein show it has a deleterious effect on protein folding, maturation, and function (Sabusap 2021). This variant is reported as pathogenic by an expert panel in ClinVar (Variation ID: 53347) and is also absent from the Genome Aggregation Database, indicating it is not a common polymorphism. The tryptophan at codon 57 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.834). Based on available information, this variant is considered to be pathogenic. References: Brancolini V et al. Search for mutations in pancreatic sufficient cystic fibrosis Italian patients: detection of 90% of molecular defects and identification of three novel mutations. Hum Genet. 1995 Sep;96(3):312-8. PMID: 7544319. Raraigh KS et al. Functional Assays Are Essential for Interpretation of Missense Variants Associated with Variable Expressivity. Am J Hum Genet. 2018 Jun 7;102(6):1062-1077. PMID: 29805046. Sabusap CM et al. The CFTR P67L variant reveals a key role for N-terminal lasso helices in channel folding, maturation, and pharmacologic rescue. J Biol Chem. 2021. Jan-Jun;296:100598. PMID: 33781744. - |
Bronchiectasis with or without elevated sweat chloride 1 Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Jun 23, 2023 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Benign
DEOGEN2
Pathogenic
D;.;.;D;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D;D;D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D;D
MetaSVM
Uncertain
D
MutationAssessor
Pathogenic
H;.;.;.;H
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;.;.;D;.
REVEL
Pathogenic
Sift
Uncertain
D;.;.;D;.
Sift4G
Benign
T;.;.;T;.
Polyphen
B;.;.;.;.
Vest4
MutPred
Loss of stability (P = 0.0125);Loss of stability (P = 0.0125);Loss of stability (P = 0.0125);Loss of stability (P = 0.0125);Loss of stability (P = 0.0125);
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at