7-117509092-C-T
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000492.4(CFTR):c.223C>T(p.Arg75Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000118 in 1,612,538 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 Pathogenic (★★★). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_000492.4 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
CFTR | NM_000492.4 | c.223C>T | p.Arg75Ter | stop_gained | 3/27 | ENST00000003084.11 | NP_000483.3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
CFTR | ENST00000003084.11 | c.223C>T | p.Arg75Ter | stop_gained | 3/27 | 1 | NM_000492.4 | ENSP00000003084 | P2 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152168Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000239 AC: 6AN: 250976Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135650
GnomAD4 exome AF: 0.0000123 AC: 18AN: 1460370Hom.: 0 Cov.: 29 AF XY: 0.00000826 AC XY: 6AN XY: 726614
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152168Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1AN XY: 74320
ClinVar
Submissions by phenotype
Cystic fibrosis Pathogenic:10
Pathogenic, criteria provided, single submitter | curation | CFTR-France | Jan 29, 2018 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 21, 2024 | This sequence change creates a premature translational stop signal (p.Arg75*) in the CFTR gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CFTR are known to be pathogenic (PMID: 1695717, 7691345, 9725922). This variant is present in population databases (rs121908749, gnomAD 0.009%). This premature translational stop signal has been observed in individual(s) with CF and cystic fibrosis (CF) (PMID: 7525450, 10923036, 18456578, 22658665, 22975760, 23276700, 23523379, 23974870, 26014425, 26574590). 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: 48672). For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center | Mar 26, 2024 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 26, 2021 | The p.R75* pathogenic mutation (also known as c.223C>T), located in coding exon 3 of the CFTR gene, results from a C to T substitution at nucleotide position 223. This changes the amino acid at codon 75 from arginine to a stop codon. This mutation was first described in a pancreatic insufficient German individual who was confirmed to have p.N1303K in trans (Dork T et al. Hum Genet. 1994;94(5):533-542). This mutation has pan-ethnic distribution (Rohlfs EM et al. Clin Chem. 2011;57(6):841-8) and is associated with elevated sweat chloride levels and pancreatic insufficiency (Sosnay PR et al. Nat Genet. 2013;45(10):1160-1167). This variant has been reported in multiple individuals with an elevated sweat chloride level in The Clinical and Functional TRanslation of CFTR (CFTR2) database (available at http://cftr2.org. Accessed 10/25/2021). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. - |
Pathogenic, reviewed by expert panel | research | CFTR2 | Mar 17, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Johns Hopkins Genomics, Johns Hopkins University | May 25, 2021 | Disease-causing CFTR variant. See www.CFTR2.org for phenotype information. - |
Pathogenic, criteria provided, single submitter | clinical testing | Genome Diagnostics Laboratory, The Hospital for Sick Children | Feb 25, 2022 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Arcensus | Feb 01, 2013 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Dec 09, 2019 | NM_000492.3(CFTR):c.223C>T(R75*) is classified as pathogenic in the context of cystic fibrosis and is associated with classic disease. Sources cited for classification include the following: PMID 7541274, 23420618, 7525450, 9806422, 22658665 and 23974870. Classification of NM_000492.3(CFTR):c.223C>T(R75*) 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. - |
Pathogenic, criteria provided, single submitter | clinical testing | Neuberg Centre For Genomic Medicine, NCGM | - | The stop-gained variant c.223C>T p.Arg75Ter in the CFTR gene has been reported in the hemizygous and heterozygous state in multiple individuals affected with Cystic Fibrosis Guo et al., 2021; Singh et al., 2015. This variant is reported with the allele frequency 0.0007% in the gnomAD Exomes and novel not in any individuals in 1000 Genomes. It has been submitted to ClinVar as Likely Pathogenic/ Pathogenic Multiple Submissions. This variant is predicted to cause a loss of normal protein function through protein truncation. Loss of function variants has been previously reported to be disease-causing. For these reasons, this variant has been classified as Pathogenic. - |
not provided Pathogenic:4
Pathogenic, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Nov 09, 2022 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Aug 22, 2022 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Oct 16, 2019 | The variant creates a premature nonsense codon, and is therefore predicted to result in the loss of a functional protein. Found in at least one patient with expected phenotype for this gene, and not found in general population data. - |
Pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Nov 20, 2023 | The CFTR c.223C>T; p.Arg75Ter variant (rs121908749) is reported in the literature in individuals affected with cystic fibrosis (Dork 1994, Sosnay 2013, CFTR2 database). This variant has been observed in affected individuals in trans to another pathogenic variant (Dork 1994) and the majority of patients described exhibit elevated sweat chloride and pancreatic insufficiency (Sosnay 2013, CFTR2 database). This variant is found on only six chromosomes (6/250976 alleles) in the Genome Aggregation Database (v2.1.1), indicating it is not a common polymorphism. This variant induces an early termination codon and 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 Dork T et al. Detection of more than 50 different CFTR mutations in a large group of German cystic fibrosis patients. Hum Genet. 1994 Nov;94(5):533-42. Sosnay PR et al. Defining the disease liability of variants in the cystic fibrosis transmembrane conductance regulator gene. Nat Genet. 2013 Oct;45(10):1160-7. - |
CFTR-related disorder Pathogenic:3
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Mar 17, 2017 | - - |
Pathogenic, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Apr 10, 2024 | The CFTR c.223C>T variant is predicted to result in premature protein termination (p.Arg75*). This variant has been reported in multiple individuals with cystic fibrosis with and without pancreatic insufficiency (see for example, Doerk et al. 1994. PubMed ID: 7525450; Wong et al. 2001. PubMed ID: 11668613; Ooi et al. 2012. PubMed ID: 22658665; Sosnay et al. 2013. PubMed ID: 23974870). This variant is reported in 0.0087% of alleles in individuals of Latino descent in gnomAD. Nonsense variants in CFTR are expected to be pathogenic. This variant is interpreted as pathogenic. - |
Pathogenic, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, The Hospital for Sick Children | Feb 25, 2022 | - - |
Cystic fibrosis;C0403814:Congenital bilateral aplasia of vas deferens from CFTR mutation Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | - | - - |
Bronchiectasis with or without elevated sweat chloride 1 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Oct 17, 2023 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at