chr7-117587811-C-T
Variant names:
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000492.4(CFTR):c.1657C>T(p.Arg553*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000971 in 1,606,458 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
Genomes: 𝑓 0.00012 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000094 ( 0 hom. )
Consequence
CFTR
NM_000492.4 stop_gained
NM_000492.4 stop_gained
Scores
2
4
1
Clinical Significance
Conservation
PhyloP100: 1.98
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]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 7-117587811-C-T is Pathogenic according to our data. Variant chr7-117587811-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 7122.Status of the report is practice_guideline, 4 stars. Variant chr7-117587811-C-T is described in Lovd as [Pathogenic]. Variant chr7-117587811-C-T is described in Lovd as [Pathogenic].
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| CFTR | NM_000492.4 | c.1657C>T | p.Arg553* | stop_gained | Exon 12 of 27 | ENST00000003084.11 | NP_000483.3 |
Ensembl
Frequencies
GnomAD3 genomes 0.000125 AC: 19AN: 152114Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000678 AC: 17AN: 250780Hom.: 0 AF XY: 0.0000885 AC XY: 12AN XY: 135534
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:30Other:1
Revision: practice guideline
LINK: link
Submissions by phenotype
Cystic fibrosis Pathogenic:15Other:1
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Dec 23, 2024 | This sequence change creates a premature translational stop signal (p.Arg553*) 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 (rs74597325, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with cystic fibrosis, congenital absence of the vas deferens, and recurrent pancreatitis (PMID: 1695717, 7693946, 9272157, 16283068, 21520337, 22658665, 23974870). 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: 7122). For these reasons, this variant has been classified as Pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | 3billion, Medical Genetics | 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: VCV000007122, PMID:1695717).It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000071, PM2_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. - |
| Pathogenic, practice guideline | curation | American College of Medical Genetics and Genomics (ACMG) | Mar 03, 2004 | - - |
| Pathogenic, reviewed by expert panel | research | CFTR2 | Mar 17, 2017 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Aug 22, 2024 | Criteria applied: PVS1,PM3_VSTR - |
| Pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Nov 12, 2019 | NM_000492.3(CFTR):c.1657C>T(R553*) is classified as pathogenic in the context of cystic fibrosis and is associated with the classic form of disease. Sources cited for classification include the following: PMID 23974870. Classification of NM_000492.3(CFTR):c.1657C>T(R553*) 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, no assertion criteria provided | literature only | OMIM | May 01, 2007 | - - |
| Pathogenic, criteria provided, single submitter | research | Center for Precision Medicine, Vanderbilt University Medical Center | Mar 16, 2018 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 29, 2022 | The p.R553* pathogenic mutation (also known as c.1657C>T), located in coding exon 12 of the CFTR gene, results from a C to T substitution at nucleotide position 1657. This changes the amino acid at codon 553 from an arginine to a stop codon. This mutation was first described in two African American individuals with cystic fibrosis, one of whom was compound heterozygous for a pathogenic CFTR mutation on the other chromosome (Cutting GR et al. Nature.1990;346(6282):366-369). One study described a homozygous individual who presented with pancreatic insufficiency (PI) and elevated sweat chloride levels (Stanke F et al. J Med Genet. 2008;45(1):47-54). This pathogenic mutation is associated with elevated sweat chloride levels, pancreatic insufficiency, and decreased lung function (Sosnay PR et al. Nat Genet. 2013;45(10):1160-1167). 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, no assertion criteria provided | clinical testing | Department of Urology, First Affiliated Hospital of Nanjing Medical University | Dec 25, 2023 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Oct 20, 2017 | The CFTR c.1657C>T (p.Arg553Ter) variant is a stop-gained variant predicted to result in premature termination of the protein. The p.Arg553Ter variant has been reported in at least 11 studies in which it is found in a total of 17 individuals with CFTR-related disorders including in three individuals in a homozygous state, in 12 individuals in a compound heterozygous state (of which at least three are related) and in one affected individual in heterozygous state. The severity of the disease varied among these individuals from very mild to severe with a range of phenotypes including classic cystic fibrosis, pancreatic insufficiency, pulmonary disease and male infertility due to congenital bilateral absence of vas deferens without pulmonary or gastrointestinal symptoms. This variant has also been reported in a heterozygous state in six unaffected relatives of affected individuals (Cutting et al. 1990a; Cutting et al 1990b; Bal et al. 1991; Cheadle et al. 1992; Will et al. 1993; Wong et al. 2004; Chen et al. 2005; Aznarez et al. 2007; Sheridan et al. 2011; Costa et al. 2011; Liu et al. 2015). The p.Arg553Ter variant was shown to result in no detectable CFTR mRNA in nasal epithelial cells and lymphocytes derived from a severely affected individual who carried the variant in a compound heterozygous state (Will et al. 1993). RT-PCR studies in patient lymphoblastoid cells lines demonstrated that the p.Arg553Ter variant results in the skipping of exon 11 through the creation of a putative exonic splicing silencer (Aznarez et al. 2007). Control data are unavailable for the p.Arg553Ter variant which is reported at a frequency of 0.000581 in the European American population of the Exome Sequencing Project. Based on the evidence and the potential impact of stop-gained variants, the pArg553Ter variant is classified as pathogenic for CFTR-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Mendelics | Nov 05, 2018 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre | Dec 17, 2024 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Nov 25, 2024 | The CFTR c.1657C>T; p.Arg553Ter variant (rs74597325) is reported in multiple cystic fibrosis patients with pancreatic insufficiency (Bal 1991, Cheadle 1992, Chen 2005, Cutting 1990, Cutting 1990b, Gallati 2009, Ooi 2012, Sheridan 2011, Sosnay 2013, CFTR2 database). Functional characterization indicates that the variant not only leads to severe mRNA depletion (Hamosh 1992), but also causes aberrant splicing (skipping of exon 11) that results in a frameshift (Aznarez 2007). This variant is reported in ClinVar (Variation ID: 7122). It is observed in the general population with an overall allele frequency of 0.007% (20/282170 alleles) in the Genome Aggregation Database. Based on available information, this variant is considered to be pathogenic. References: CFTR2 database: http://cftr2.org Aznarez I et al. Exon skipping through the creation of a putative exonic splicing silencer as a consequence of the cystic fibrosis mutation R553X. J Med Genet. 2007 May;44(5):341-6. Bal J et al. A cystic fibrosis patient homozygous for the nonsense mutation R553X. J Med Genet. 1991 Oct;28(10):715-7. Cheadle J et al. Mild pulmonary disease in a cystic fibrosis child homozygous for R553X. J Med Genet. 1992 Aug;29(8):597. Chen HJ et al. Cystic fibrosis with homozygous R553X mutation in a Taiwanese child. J Hum Genet. 2005;50(12):674-8. Cutting GR et al. A cluster of cystic fibrosis mutations in the first nucleotide-binding fold of the cystic fibrosis conductance regulator protein. Nature. 1990 Jul 26;346(6282):366-9. Cutting GR et al. Two patients with cystic fibrosis, nonsense mutations in each cystic fibrosis gene, and mild pulmonary disease. N Engl J Med. 1990b Dec 13;323(24):1685-9. Gallati S et al Cystic fibrosis transmembrane conductance regulator mutations in azoospermic and oligospermic men and their partners. Reprod Biomed Online. 2009 Nov;19(5):685-94. Hamosh A et al. CFTR nonsense mutations G542X and W1282X associated with severe reduction of CFTR mRNA in nasal epithelial cells. Hum Mol Genet. 1992 Oct;1(7):542-4. Ooi CY et al. Cystic fibrosis transmembrane conductance regulator (CFTR) gene mutations in pancreatitis. J Cyst Fibros. 2012 Sep;11(5):355-62. Sheridan MB et al. CFTR transcription defects in pancreatic sufficient cystic fibrosis patients with only one mutation in the coding region of CFTR. J Med Genet. 2011 Apr;48(4):235-41. 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. - |
| Pathogenic, criteria provided, single submitter | curation | CFTR-France | Jan 29, 2018 | - - |
not provided Pathogenic:7
| Pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Jan 17, 2023 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Aug 15, 2017 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Oct 14, 2021 | This nonsense variant causes the premature termination of CFTR protein synthesis. In the published literature, the variant has been reported in individuals affected with CF or a CFTR-related disease (PMID: 1695717 (1990), 23974870 (2013), 25580864 (2015), 29590070 (2018)). Based on the available information, this variant is classified as pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Clinical Genetics Laboratory, Skane University Hospital Lund | May 27, 2022 | - - |
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 | Oct 03, 2023 | The CFTR c.1657C>T variant is predicted to result in premature protein termination (p.Arg553*). This variant is documented causative for cystic fibrosis (see, for example, Cutting et al. 1990. PubMed ID: 1695717). This variant is reported in 0.012% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/7-117227865-C-T). Nonsense variants in CFTR are expected to be pathogenic. This variant is interpreted as pathogenic. - |
Cystic fibrosis;C0403814:Congenital bilateral aplasia of vas deferens from CFTR mutation Pathogenic:2
| Pathogenic, criteria provided, single submitter | clinical testing | Juno Genomics, Hangzhou Juno Genomics, Inc | - | PM2_Supporting+PVS1+PM3_VeryStrong - |
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | - | - - |
Bronchiectasis with or without elevated sweat chloride 1 Pathogenic:2
| Pathogenic, criteria provided, single submitter | clinical testing | Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein | Oct 29, 2022 | ACMG classification criteria: PVS1 very strong, PM2 supporting, PM3 strong, PP1 supporting - |
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 26, 2024 | - - |
not specified Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Oct 06, 2017 | Variant summary: The CFTR c.1657C>T (p.Arg553X) variant results in a premature termination codon, predicted to cause a truncated or absent CFTR protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g., c.1742dupT [p.Leu581fsX8] and c.1792_1798delAAAACTA [p.Lys598fsX11]). One in silico tool predicts a damaging outcome for this variant. This variant was found in 21/276546 control chromosomes at a frequency of 0.0000759, which does not exceed the estimated maximal expected allele frequency of a pathogenic CFTR variant (0.0129603). This variant is a well-characterized, disease-causing mutation in CFTR - in a study of 39,696 individuals with cystic fibrosis in registries and clinics in North America and Europe, the variant was present in 645 CF patients; and of the 369 patients included in the analsyis, 96.1% were pancreatic insufficient (Sosnay_2013). RNA from nasal epithelial cells of a patient with the genotype S549N/R553X showed that <2% of the transcripts were derived from R553X (Hamosh_1991). Additionally, chloride secretion in a rectal biopsy specimens from 3 patients with the genotype deltaF508/R553X found that Cl-secretion was 0% of control, suggesting that R553X is non-functional (Hirtz_2004). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. - |
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 | Jan 03, 2024 | - - |
Computational scores
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BayesDel_addAF
Pathogenic
D
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Pathogenic
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Pathogenic
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Uncertain
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Uncertain
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Uncertain
D
Vest4
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Details are displayed if max score is > 0.2
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Find out detailed SpliceAI scores and Pangolin per-transcript scores at