7-117627537-C-T

Variant names:

• chr7-117627537-C-T
• rs74767530
• NM_000492.4:c.3484C>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.3484C>T​(p.Arg1162*) 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:
  • Genomes: 𝑓 0.000046 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000046 (0 hom.)
• Consequence: CFTR NM_000492.4 stop_gained
• Clinical Significance: Pathogenic practice guideline P:26 O:1
• Conservation: PhyloP100: 1.53

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 7-117627537-C-T is Pathogenic according to our data. Variant chr7-117627537-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 7137.Status of the report is practice_guideline, 4 stars. Variant chr7-117627537-C-T is described in Lovd as [Pathogenic]. Variant chr7-117627537-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.3484C>T	p.Arg1162*	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.3484C>T	p.Arg1162*	stop_gained	Exon 22 of 27	1	NM_000492.4	ENSP00000003084.6

Frequencies

GnomAD3 genomes AF: 0.0000460 AC: 7 AN: 152030 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000559 AC: 14 AN: 250612 Hom.: 0 AF XY: 0.0000738 AC XY: 10 AN XY: 135436

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: 0.000229

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000530

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.0000459 AC: 67 AN: 1460898 Hom.: 0 Cov.: 31 AF XY: 0.0000482 AC XY: 35 AN XY: 726736

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000896

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000267

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.0000306

Gnomad4 OTH exome AF: 0.0000829

GnomAD4 genome AF: 0.0000460 AC: 7 AN: 152030 Hom.: 0 Cov.: 32 AF XY: 0.0000673 AC XY: 5 AN XY: 74252

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000855 Hom.: 0

Bravo AF: 0.0000604

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000494 AC: 6

EpiCase AF: 0.000109

EpiControl AF: 0.000237

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:26 Other:1

Revision: practice guideline

Submissions by phenotype

Cystic fibrosis Pathogenic:12 Other:1

Nov 05, 2018

Mendelics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Mar 03, 2004

American College of Medical Genetics and Genomics (ACMG)

Significance: Pathogenic

Review Status: practice guideline

Collection Method: curation

- -

Jan 05, 2022

DASA

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Dec 26, 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.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. -

Jan 29, 2018

CFTR-France

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Mar 17, 2017

CFTR2

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: research

- -

Nov 12, 2019

Myriad Genetics, Inc.

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Jan 03, 2022

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Aug 01, 1992

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Sep 18, 2021

Genetics and Genomic Medicine Centre, NeuroGen Healthcare, NeuroGen Healthcare

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 04, 2023

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

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Neuberg Centre For Genomic Medicine, NCGM

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The observed stop gained c.3484C>T(p.Arg1162Ter) variant has been reported previously in multiple individuals affected with cystic fibrosis (Shahin et al., 2016; Sosnay et al., 2013; Sorio et al., 2011; Jézéquel et al., 2000). Experimental studies show that lack of full length CFTR protein and improper localization of the truncated form at the plasma membrane in cells result in an absent or disrupted protein product (Sorio et al., 2011). This variant is present with an allele frequency of 0.006% in gnomAD Exomes database. This variant has been submitted to the ClinVar database as Pathogenic (multiple submissions). Computational evidence (MutationTaster - disease causing) predict a damaging effect on protein structure and function for this variant. The reference amino acid of p.Arg1162Ter in CFTR is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. This sequence change creates a premature translational stop signal (p.Arg1162Ter). Loss of function variants in CFTR gene have been previously reported to be disease causing (Yang et al., 1993). For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:7

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Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

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

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Aug 28, 2018

Clinical Genetics and Genomics, Karolinska University Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 13, 2022

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: criteria provided, single submitter

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

- -

Jan 05, 2017

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 04, 2020

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

CFTR-related disorder Pathogenic:2

Mar 17, 2017

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jun 04, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

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; Table 1, Raraigh et al. 2021. PubMed ID: 34782259; Table 2, Chernykh et al. 2023. PubMed ID: 38003474). 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

Mar 14, 2018

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

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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

Feb 06, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Bronchiectasis with or without elevated sweat chloride 1 Pathogenic:1

Mar 30, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Congenital bilateral aplasia of vas deferens from CFTR mutation Pathogenic:1

May 20, 2023

Neuberg Centre For Genomic Medicine, NCGM

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The observed stop gain c.3484C>T(p.Arg1162Ter) variant has been reported in heterozygous state in individuals affected with CFTR related disease (Sosnay PR, et. al., 2013; Sorio C, et. al., 2011; Jézéquel P, et. al., 2000). Experimental studies show that lack of full length CFTR protein and improper localization of the truncated form at the plasma membrane in cells result in an absent or disrupted protein product (Sorio C, et. al., 2011). This variant is present with an allele frequency of 0.006% in gnomAD Exomes database. This variant has been submitted to the ClinVar database as Pathogenic (multiple submissions). Computational evidence (MutationTaster - disease causing) predict a damaging effect on protein structure and function for this variant. The nucleotide change c.3484C>T in CFTR is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. This sequence change creates a premature translational stop signal (p.Arg1162Ter). Loss of function variants have been previously reported to be disease causing (Yang Y, et. al., 1993). For these reasons, this variant has been classified as Pathogenic. In absence of another reportable variant in CFTR gene, the molecular diagnosis is not confirmed. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.62
CADD	Pathogenic	39
DANN	Uncertain	1.0
Eigen	Uncertain	0.68
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Uncertain	0.97	D
Vest4		0.95
GERP RS		3.8

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs74767530; hg19: chr7-117267591;