chr7-117627537-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.3484C>T(p.Arg1162Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000459 in 1,612,928 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 | UniProt |
---|---|---|---|---|---|---|---|
CFTR | NM_000492.4 | c.3484C>T | p.Arg1162Ter | stop_gained | 22/27 | ENST00000003084.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CFTR | ENST00000003084.11 | c.3484C>T | p.Arg1162Ter | stop_gained | 22/27 | 1 | NM_000492.4 | P2 | |
ENST00000456270.1 | n.66-11197G>A | intron_variant, non_coding_transcript_variant | 3 |
Frequencies
GnomAD3 genomes AF: 0.0000460 AC: 7AN: 152030Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000559 AC: 14AN: 250612Hom.: 0 AF XY: 0.0000738 AC XY: 10AN XY: 135436
GnomAD4 exome AF: 0.0000459 AC: 67AN: 1460898Hom.: 0 Cov.: 31 AF XY: 0.0000482 AC XY: 35AN XY: 726736
GnomAD4 genome AF: 0.0000460 AC: 7AN: 152030Hom.: 0 Cov.: 32 AF XY: 0.0000673 AC XY: 5AN XY: 74252
ClinVar
Submissions by phenotype
Cystic fibrosis Pathogenic:11Other:1
Pathogenic, practice guideline | curation | American College of Medical Genetics and Genomics (ACMG) | Mar 03, 2004 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Mendelics | Nov 05, 2018 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Nov 12, 2019 | NM_000492.3(CFTR):c.3484C>T(R1162*) is classified as pathogenic in the context of cystic fibrosis and is associated with the classic form of this disease. Sources cited for classification include the following: PMID 23974870. Classification of NM_000492.3(CFTR):c.3484C>T(R1162*) 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. - |
not provided, no classification provided | literature only | GeneReviews | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Neuberg Centre For Genomic Medicine, NCGM | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | DASA | Jan 05, 2022 | The c.3484C>T;p.(Arg1162*) variant creates a premature translational stop signal in the CFTR gene. It is expected to result in an absent or disrupted protein product -PVS1. This sequence change has been observed in affected individual(s) and ClinVar contains an entry for this variant(ClinVar ID: 7137; PMID: 20301428; 21416780; 15994263; 11101688; 20301428; 21811577; 7526685) - PS4. The variant is present at low allele frequencies population databases (rs74767530 – gnomAD 0.004604%; ABraOM 0.000427 frequency - http://abraom.ib.usp.br/) - PM2_supporting. The p.(Arg1162*) was detected in trans with a pathogenic variant(PMID: 21811577) - PM3. In summary, the currently available evidence indicates that the variant is pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | 3billion | Jan 03, 2022 | Stop-gained (nonsense): predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant (PVS1_VS). The variant has been reported multiple times as an established pathogenic/likely pathogenic variant (ClinVar ID: VCV000007137, PMID:2045102). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000057, PM2_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. - |
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 04, 2023 | The p.R1162* pathogenic mutation (also known as c.3484C>T), located in coding exon 22 of the CFTR gene, results from a C to T substitution at nucleotide position 3484. This changes the amino acid from an arginine to a stop codon within coding exon 22. This mutation has been reported in the homozygous state in nine individuals with pancreatic insufficiency and mild to moderate pulmonary symptoms (Gasparini P et al. J. Med. Genet., 1992 Aug;29:558-62). This pathogenic mutation is associated with elevated sweat chloride levels, pancreatic insufficiency, and decreased lung function (Sosnay PR et al. Nat. Genet., 2013 Oct;45:1160-7; Shahin WA et al. Springerplus, 2016 May;5:686). 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, no assertion criteria provided | literature only | OMIM | Aug 01, 1992 | - - |
Pathogenic, criteria provided, single submitter | curation | CFTR-France | Jan 29, 2018 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 16, 2024 | This sequence change creates a premature translational stop signal (p.Arg1162*) 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 (rs74767530, gnomAD 0.02%). This premature translational stop signal has been observed in individual(s) with cystic fibrosis (CF) and is included in the American College of Medical Genetics (ACMG) panel of CF variants (PMID: 15371902, 23974870). ClinVar contains an entry for this variant (Variation ID: 7137). For these reasons, this variant has been classified as Pathogenic. - |
not provided Pathogenic:7
Pathogenic, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | May 13, 2022 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Clinical Genetics and Genomics, Karolinska University Hospital | Aug 28, 2018 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Jan 05, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Apr 04, 2020 | The CFTR c.3484C>T; p.Arg1162Ter variant (rs74767530) has been reported in patients diagnosed with cystic fibrosis, and is often associated with pancreatic insufficiency (Gasparini 1991, Gasparini 1992, Ooi 2012, Sosnay 2013, CFTR2 database). This variant is reported in ClinVar (Variation ID: 7137), and is found in the general population with an overall allele frequency of 0.0057% (16/281996 alleles) in the Genome Aggregation Database. 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, the p.Arg1162Ter variant is considered to be pathogenic. References: CFTR2 database: http://cftr2.org/ Gasparini P et al. The search for south European cystic fibrosis mutations: identification of two new mutations, four variants, and intronic sequences. Genomics. 1991; 10(1):193-200. Gasparini P et al. Nine cystic fibrosis patients homozygous for the CFTR nonsense mutation R1162X have mild or moderate lung disease. J Med Genet. 1992; 29(8):558-62. Ooi C. et al. Cystic fibrosis transmembrane conductance regulator (CFTR) gene mutations in pancreatitis. J Cyst Fibros. 2012; 11(5):355-62. Sosnay PR et al. Defining the disease liability of variants in the cystic fibrosis transmembrane conductance regulator gene. Nat Genet. 2013; 45(10):1160-7. - |
Pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Pathogenic, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
CFTR-related disorder Pathogenic:2
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Mar 17, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Feb 14, 2024 | The CFTR c.3484C>T variant is predicted to result in premature protein termination (p.Arg1162*). This variant has been repeatedly reported to be causative for cystic fibrosis (see for example Gasparini et al. 1991. PubMed ID: 2045102; Sosnay et al. 2013. PubMed ID: 23974870). This variant is reported in 0.023% of alleles in individuals of South Asian descent in gnomAD. Nonsense variants in CFTR are expected to be pathogenic. This variant is interpreted as pathogenic. - |
not specified Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Mar 14, 2018 | Variant summary: CFTR c.3484C>T (p.Arg1162X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 5.4e-05 in 276330 control chromosomes. The c.3484C>T variant has been reported in the literature in numerous individuals affected with Cystic Fibrosis and is considered a common pathogenic mutation (see e.g. Sosnay 2013, Gasparini 1991). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence, which showed the lack of full length CFTR protein and improper localization of the truncated form at the plasma membrane in cells from a homozygous patient (Sorio 2011). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and all laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Cystic fibrosis;C0403814:Congenital bilateral aplasia of vas deferens from CFTR mutation Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | - | - - |
Cystic fibrosis;C0238339:Hereditary pancreatitis;C0403814:Congenital bilateral aplasia of vas deferens from CFTR mutation;C2749757:Bronchiectasis with or without elevated sweat chloride 1 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Aug 04, 2021 | - - |
Bronchiectasis with or without elevated sweat chloride 1 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 30, 2024 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at