7-117587811-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.1657C>T​(p.Arg553Ter) 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

Scores

2
4
1

Clinical Significance

Pathogenic practice guideline P:28O:1

Conservation

PhyloP100: 1.98
Variant links:
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 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/exons MANE Protein UniProt
CFTRNM_000492.4 linkuse as main transcriptc.1657C>T p.Arg553Ter stop_gained 12/27 ENST00000003084.11 NP_000483.3

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
CFTRENST00000003084.11 linkuse as main transcriptc.1657C>T p.Arg553Ter stop_gained 12/271 NM_000492.4 ENSP00000003084 P2P13569-1

Frequencies

GnomAD3 genomes
AF:
0.000125
AC:
19
AN:
152114
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000121
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.000192
Gnomad SAS
AF:
0.000207
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000147
Gnomad OTH
AF:
0.000956
GnomAD3 exomes
AF:
0.0000678
AC:
17
AN:
250780
Hom.:
0
AF XY:
0.0000885
AC XY:
12
AN XY:
135534
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000327
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000124
Gnomad OTH exome
AF:
0.000327
GnomAD4 exome
AF:
0.0000942
AC:
137
AN:
1454226
Hom.:
0
Cov.:
27
AF XY:
0.000105
AC XY:
76
AN XY:
724050
show subpopulations
Gnomad4 AFR exome
AF:
0.0000601
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000464
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.000116
Gnomad4 OTH exome
AF:
0.0000499
GnomAD4 genome
AF:
0.000125
AC:
19
AN:
152232
Hom.:
0
Cov.:
32
AF XY:
0.000134
AC XY:
10
AN XY:
74428
show subpopulations
Gnomad4 AFR
AF:
0.000120
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.000193
Gnomad4 SAS
AF:
0.000207
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000147
Gnomad4 OTH
AF:
0.000946
Alfa
AF:
0.000163
Hom.:
0
Bravo
AF:
0.000147
TwinsUK
AF:
0.000270
AC:
1
ALSPAC
AF:
0.000259
AC:
1
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000581
AC:
5
ExAC
AF:
0.000124
AC:
15
Asia WGS
AF:
0.000289
AC:
1
AN:
3478
EpiCase
AF:
0.000273
EpiControl
AF:
0.000178

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:28Other:1
Revision: practice guideline
LINK: link

Submissions by phenotype

Cystic fibrosis Pathogenic:13Other:1
Pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 18, 2024This 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 submitterclinical testing3billionJan 03, 2022Stop-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 guidelinecurationAmerican College of Medical Genetics and Genomics (ACMG)Mar 03, 2004- -
Pathogenic, no assertion criteria providedliterature onlyOMIMMay 01, 2007- -
Pathogenic, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaOct 20, 2017The 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, reviewed by expert panelresearchCFTR2Mar 17, 2017- -
not provided, no classification providedliterature onlyGeneReviews-- -
Pathogenic, criteria provided, single submitterclinical testingAmbry GeneticsJun 29, 2022The 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, criteria provided, single submitterclinical testingInstitute of Human Genetics, University of Leipzig Medical CenterAug 22, 2024Criteria applied: PVS1,PM3_VSTR -
Pathogenic, criteria provided, single submitterclinical testingMyriad Genetics, Inc.Nov 12, 2019NM_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. -
Pathogenic, criteria provided, single submitterclinical testingMendelicsNov 05, 2018- -
Pathogenic, criteria provided, single submitterresearchCenter for Precision Medicine, Vanderbilt University Medical CenterMar 16, 2018- -
Pathogenic, criteria provided, single submittercurationCFTR-FranceJan 29, 2018- -
Pathogenic, no assertion criteria providedclinical testingDepartment of Urology, First Affiliated Hospital of Nanjing Medical UniversityDec 25, 2023- -
not provided Pathogenic:8
Pathogenic, no assertion criteria providedclinical testingClinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center-- -
Pathogenic, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)Aug 15, 2017- -
Pathogenic, criteria provided, single submitterclinical testingQuest Diagnostics Nichols Institute San Juan CapistranoOct 14, 2021This 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, no assertion criteria providedclinical testingDiagnostic Laboratory, Department of Genetics, University Medical Center Groningen-- -
Pathogenic, criteria provided, single submitterclinical testingMayo Clinic Laboratories, Mayo ClinicJan 17, 2023- -
Pathogenic, no assertion criteria providedclinical testingJoint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+-- -
Pathogenic, criteria provided, single submitterclinical testingClinical Genetics Laboratory, Skane University Hospital LundMay 27, 2022- -
Pathogenic, criteria provided, single submitterclinical testingARUP Laboratories, Molecular Genetics and Genomics, ARUP LaboratoriesOct 23, 2023The 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. -
CFTR-related disorder Pathogenic:2
Pathogenic, no assertion criteria providedclinical testingNatera, Inc.Mar 17, 2017- -
Pathogenic, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact SciencesOct 03, 2023The 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. -
Bronchiectasis with or without elevated sweat chloride 1 Pathogenic:2
Pathogenic, criteria provided, single submitterclinical testingBaylor GeneticsMar 26, 2024- -
Pathogenic, criteria provided, single submitterclinical testingLaboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert EinsteinOct 29, 2022ACMG classification criteria: PVS1 very strong, PM2 supporting, PM3 strong, PP1 supporting -
not specified Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpOct 06, 2017Variant 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;C0403814:Congenital bilateral aplasia of vas deferens from CFTR mutation Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingBaylor 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 submitterclinical testingFulgent Genetics, Fulgent GeneticsApr 13, 2022- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.46
D
BayesDel_noAF
Pathogenic
0.54
CADD
Pathogenic
39
DANN
Uncertain
1.0
Eigen
Uncertain
0.67
Eigen_PC
Uncertain
0.52
FATHMM_MKL
Uncertain
0.86
D
MutationTaster
Benign
1.0
A;A
Vest4
0.93
GERP RS
4.4

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.21
Details are displayed if max score is > 0.2
DS_DL_spliceai
0.21
Position offset: 22

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs74597325; hg19: chr7-117227865; API