7-117627525-C-T

Variant names:

• chr7-117627525-C-T
• rs79850223
• NM_000492.4:c.3472C>T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000492.4(CFTR):​c.3472C>T​(p.Arg1158*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000279 in 1,612,844 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 0.000026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000028 (0 hom.)
• Consequence: CFTR NM_000492.4 stop_gained
• Clinical Significance: Pathogenic reviewed by expert panel P:22
• Conservation: PhyloP100: 3.37

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]

ENSG00000083622 (HGNC:):

ACMG classification

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 7-117627525-C-T is Pathogenic according to our data. Variant chr7-117627525-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 7144.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr7-117627525-C-T is described in Lovd as [Pathogenic]. Variant chr7-117627525-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.3472C>T	p.Arg1158*	stop_gained	Exon 22 of 27	ENST00000003084.11	NP_000483.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CFTR	ENST00000003084.11	c.3472C>T	p.Arg1158*	stop_gained	Exon 22 of 27	1	NM_000492.4	ENSP00000003084.6

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152110 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000319 AC: 8 AN: 250472 Hom.: 0 AF XY: 0.0000443 AC XY: 6 AN XY: 135370

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000131

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000265

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000281 AC: 41 AN: 1460734 Hom.: 0 Cov.: 31 AF XY: 0.0000344 AC XY: 25 AN XY: 726666

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000139

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000216

Gnomad4 OTH exome AF: 0.0000332

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152110 Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3 AN XY: 74298

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000375 Hom.: 0

Bravo AF: 0.0000340

ExAC AF: 0.0000412 AC: 5

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:22

Revision: reviewed by expert panel

Submissions by phenotype

Cystic fibrosis Pathogenic:10

Nov 05, 2018

Mendelics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 17, 2017

CFTR2

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: research

- -

Oct 04, 2024

Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

PVS1(strong),PM3(strong),PM2 -

Dec 18, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 01, 1992

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Jan 29, 2018

CFTR-France

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Sep 28, 2016

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: The CFTR c.3472C>T (p.Arg1158X) 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 in CF or CFTR-related diseases. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g. p.Arg1162X, p.Gln1382X, p.Ser1455X, etc.). This variant was found in 5/120064 control chromosomes at a frequency of 0.0000416, which does not exceed the estimated maximal expected allele frequency of a pathogenic CFTR variant (0.0129603). This variant has been reported in many affected individuals with CF and CF-RDs (Amato_2012, Sosnay_2013). Multiple clinical diagnostic laboratories/reputable databases have classified this variant as pathogenic. Taken together, this variant is classified as Pathogenic. -

Sep 13, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Arg1158*) 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 (rs79850223, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with cystic fibrosis and/or congenital bilateral absence of the vas deferens (PMID: 22020151, 22658665, 23974870). ClinVar contains an entry for this variant (Variation ID: 7144). For these reasons, this variant has been classified as Pathogenic. -

Nov 11, 2019

Myriad Genetics, Inc.

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

NM_000492.3(CFTR):c.3472C>T(R1158*) 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 and 21909392. Classification of NM_000492.3(CFTR):c.3472C>T(R1158*) 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.‚Äã -

Jul 06, 2022

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.R1158* pathogenic mutation (also known as c.3472C>T) is located in coding exon 22 of the CFTR gene. This alteration results from a C to T substitution at nucleotide position 3472. The arginine at codon 1158 is replaced by a stop codon within coding exon 22. This alteration has been reported in individuals with cystic fibrosis (Ronchetto P et al. Genomics. 1992;12(2):417-418; Castaldo G et al. Clin Chem. 1999;45(7):957-962; Frossard et al. Clin Genet. 2000;58:147-9; Sosnay PR et al. Nat Genet. 2013;45(10):1160-7). 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. -

not provided Pathogenic:6

Aug 10, 2020

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 found in general population data at a frequency that is consistent with pathogenicity. -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Oct 04, 2017

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The CFTR c.3472C>T; p.Arg1158Ter variant is reported in the medical literature in individuals with cystic fibrosis and related disorders (Amato 2012, Frossard 2000, Ooi 2012, Sosnay 2013). The variant is listed in the ClinVar database (Variation ID: 7144), in the dbSNP variant database (rs79850223), and in the Genome Aggregation Database with a low population frequency (8/245236 alleles). This variant introduces a premature termination codon and is predicted to result in a truncated protein or mRNA subject to non-sense mediated decay. Considering available information, this variant is classified as severely pathogenic. References: Amato F et al. Extensive molecular analysis of patients bearing CFTR-related disorders. J Mol Diagn. 2012 Jan;14(1):81-9. Frossard PM et al. Mild clinical phenotype associated with R1158X/S549R(T-->G) CFTR genotype. Clin Genet. 2000 Aug;58(2):147-9. Ooi CY and Durie PR. Cystic fibrosis transmembrane conductance regulator (CFTR) gene mutations in pancreatitis. J Cyst Fibros. 2012 Sep;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 Oct;45(10):1160-7. -

Jun 16, 2017

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The R1158X variant in the CFTR gene has been reported previously in association with cystic fibrosis (Ronchetto et al., 1992; Frossard et al., 2000; Ooi et al., 2012; Sosnay et al., 2013). This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The R1158X variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). We interpret R1158X as a pathogenic variant. -

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

CFTR-related disorder Pathogenic:2

Mar 17, 2017

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Oct 06, 2022

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The CFTR c.3472C>T variant is predicted to result in premature protein termination (p.Arg1158*). This variant has been reported in many unrelated individuals to be causative for cystic fibrosis and CFTR-related diseases (Ronchetto et al.1992. PubMed ID: 1371265; Frossard et al. 2000. PubMed ID: 11005149; Amato et al. 2012. PubMed ID: 22020151; Ooi et al. 2012. PubMed ID: 22658665; Sosnay et al. 2013. PubMed ID: 23974870). This variant is reported in 0.013% of alleles in individuals of South Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/7-117267579-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

Dec 13, 2023

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

A heterozygous variant in exon 22 of the CFTR gene that results in the premature protein termination (p.Arg1158Ter) was detected. The observed variant c.3472C>T(p.Arg1158Ter) has been reported in the 1000 genomes and has a MAF of 0.003% in the gnomAD database. The in-silico prediction of the variant is damaging by MutationTaster2. In summary, the variant meets our criteria to be classified as pathogenic. -

Cystic fibrosis;C0403814:Congenital bilateral aplasia of vas deferens from CFTR mutation Pathogenic:1

-

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Jan 30, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.63
CADD	Pathogenic	38
DANN	Uncertain	1.0
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Pathogenic	0.98	D
Vest4		0.94
GERP RS		3.9

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs79850223; hg19: chr7-117267579; COSMIC: COSV50107726;