7-117530974-C-T

Position:

chr7-117530974-C-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PM5PP3_ModeratePP5_Very_Strong

The NM_000492.4(CFTR):c.349C>T(p.Arg117Cys) variant causes a missense change. The variant allele was found at a frequency of 0.000102 in 1,613,580 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,drug response (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R117G) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00010 ( 0 hom. )

Consequence

CFTR
NM_000492.4 missense

Scores

Clinical Significance

Pathogenic; drug response reviewed by expert panel P:24O:2

Conservation

PhyloP100: 3.82

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]

CFTR links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 ACMG points.

PM1

In a topological_domain Extracellular (size 23) in uniprot entity CFTR_HUMAN there are 19 pathogenic changes around while only 0 benign (100%) in NM_000492.4

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr7-117530974-C-G is described in Lovd as [Likely_pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.858

PP5

Variant 7-117530974-C-T is Pathogenic according to our data. Variant chr7-117530974-C-T is described in ClinVar as [Pathogenic, drug_response]. Clinvar id is 48688.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr7-117530974-C-T is described in Lovd as [Pathogenic]. Variant chr7-117530974-C-T is described in Lovd as [Pathogenic]. Variant chr7-117530974-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CFTR	NM_000492.4 linkuse as main transcript	c.349C>T	p.Arg117Cys	missense_variant	4/27	ENST00000003084.11	NP_000483.3	P13569-1A0A024R730

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CFTR	ENST00000003084.11 linkuse as main transcript	c.349C>T	p.Arg117Cys	missense_variant	4/27	1	NM_000492.4	ENSP00000003084.6		P13569-1

Frequencies

GnomAD3 genomes

AF:

0.000105

AC:

AN:

152174

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000206

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000203

AC:

AN:

250944

Hom.:

AF XY:

0.000243

AC XY:

AN XY:

135604

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000290

Gnomad ASJ exome

AF:

0.0000993

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000654

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000414

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000102

AC:

149

AN:

1461406

Hom.:

Cov.:

AF XY:

0.000111

AC XY:

AN XY:

726994

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000448

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000464

Gnomad4 FIN exome

AF:

0.0000562

Gnomad4 NFE exome

AF:

0.000120

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.000105

AC:

AN:

152174

Hom.:

Cov.:

AF XY:

0.000108

AC XY:

AN XY:

74330

show subpopulations

Gnomad4 AFR

AF:

0.0000483

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000206

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000139

Hom.:

Bravo

AF:

0.000113

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000346

AC:

EpiCase

AF:

0.000164

EpiControl

AF:

0.000178

ClinVar

Significance: Pathogenic; drug response

Submissions summary: Pathogenic:24Other:2

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Cystic fibrosis

Pathogenic:9Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 22, 2024	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 117 of the CFTR protein (p.Arg117Cys). This variant is present in population databases (rs77834169, gnomAD 0.04%). This missense change has been observed in individual(s) with congenital bilateral absence of the vas deferens and/or cystic fibrosis (PMID: 7525450, 7529962, 11788090, 15482777, 21520337, 21783433, 22658665, 23974870, 24586523). 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: 48688). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt CFTR protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects CFTR function (PMID: 18449561, 20932301, 23891399, 23974870). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Genomic Research Center, Shahid Beheshti University of Medical Sciences	May 03, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 30, 2021	The p.R117C pathogenic mutation (also known as c.349C>T), located in coding exon 4 of the CFTR gene, results from a C to T substitution at nucleotide position 349. The arginine at codon 117 is replaced by cysteine, an amino acid with highly dissimilar properties. This mutation was first described in a 12-year-old cystic fibrosis (CF) patient with elevated sweat chloride levels and pancreatic sufficiency, who was confirmed to carry a pathogenic CFTR mutation on the other allele (Dörk T et al. Hum Genet. 1994;94(5):533-42). In one study in the Swedish population, this mutation was identified in 7 patients with elevated sweat chloride levels and pancreatic sufficiency (PS); each had p.F508del on the other chromosome (in trans) (Strandvik B et al. Genet Test. 2001;5(3):235-42). Another study report this mutation 67 patients who were compound heterozygous for another CF-causing mutation. These patients predominantly had normal lung function, elevated sweat chloride levels, and pancreatic sufficiency (Sosnay PR et al. Nat Genet. 2013;45(10):1160-7). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -
Pathogenic, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, The Hospital for Sick Children	Jun 18, 2019	- -
not provided, no classification provided	phenotyping only	GenomeConnect, ClinGen	-	Variant interpretted as Pathogenic and reported on 10-07-2019 by Lab or GTR ID 1197. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -
Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 22, 2021	- -
Pathogenic, reviewed by expert panel	research	CFTR2	Mar 17, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 11, 2019	Across a selection of the available literature, the CFTR c.349C>T (p.Arg117Cys) missense variant has been identified in a total of 17 individuals, including in a homozygous state in three with cystic fibrosis (CF) and in a compound heterozygous state in 11 with CF and three individuals with congenital bilateral absence of the vas deferens (CBAVD) (DÃ¶rk et al. 1994; Massie et al. 2001; Wilschanski et al. 2006; Steiner et al. 2011; Costa et al. 2011; Schippa et al. 2013; ZiÄ™tkiewicz et al. 2014; Lundman et al. 2016). The p.Arg117Cys variant was frequently found in trans with p.Phe508del variant. The p.Arg117Cys variant is also reported in 141 individuals in the CFTR2 database (http://cftr2.org/). Control data are unavailable for this variant, which is reported at a frequency of 0.000388 in the European (non-Finnish) population of the Genome Aggregation Database. Sosnay et al. (2013) and Van Goor et al. (2014) demonstrated that the p.Arg117Cys variant resulted in significantly reduced chloride ion conductance and transport, as compared to wild type. The pathogenicity of the p.Arg117Cys variant is affected by a specific intronic variation in CFTR, termed the poly-T tract, which occurs in three forms (5T/7T/9T). Depending on which poly-T form is present in the same copy of the CFTR gene with p.Arg117Cys, differing clinical outcomes may occur. Based on the evidence, the p.Arg117Cys 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	Counsyl	Nov 24, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	Nov 05, 2018	- -

not provided

Pathogenic:8

Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Apr 25, 2023	The CFTR c.349C>T; p.Arg117Cys variant (rs77834169) is reported in the literature in multiple individuals affected with cystic fibrosis (Claustres 2000, Costa 2011, Gonska 2009, McGinniss 2005, Sosnay 2013, Strandvik 2001, Wong 2004), and is often associated with pancreatic sufficiency (Sosnay 2013, CFTR2 database) and borderline sweat chloride (Lebecque 2002, Sontag 2005, Wong 2004). However, this variant has also been identified in patients with CFTR-related disorders, such as congenital bilateral absence of vas deferens (Claustres 2000, Mercier 1995, Steiner 2011, Wilschanski 2006, Zielenski 1995), and in asymptomatic individuals even when found with another pathogenic variant on the opposite chromosome (Wong 2004). This variant is reported in ClinVar (Variant ID: 48688), and is found in the general population with an overall allele frequency of 0.018% (52/282344 alleles) in the Genome Aggregation database. Computational analyses predict that this variant is deleterious (REVEL: 0.823). Functional characterization of the variant protein indicates a defect in chloride transport (Cui 2014, Sosnay 2013, van Goor 201408). Based on available information, this variant is considered to be pathogenic with varying clinical consequences. References: CFTR2 database: http://cftr2.org/ Claustres M et al. Spectrum of CFTR mutations in cystic fibrosis and in congenital absence of the vas deferens in France. Hum Mutat. 2000; 16(2):143-56. PMID: 10923036. Costa C et al. A recurrent deep-intronic splicing CF mutation emphasizes the importance of mRNA studies in clinical practice. J Cyst Fibros. 2011; 10(6):479-82. PMID: 21783433. Cui G et al. Three charged amino acids in extracellular loop 1 are involved in maintaining the outer pore architecture of CFTR. J Gen Physiol. 2014; 144(2):159-79. PMID: 25024266. Gonska T et al. Sweat gland bioelectrics differ in cystic fibrosis: a new concept for potential diagnosis and assessment of CFTR function in cystic fibrosis. Thorax. 2009; 64(11):932-8. PMID: 19734129. Lebecque P et al. Mutations of the cystic fibrosis gene and intermediate sweat chloride levels in children. Am J Respir Crit Care Med. 2002; 165(6):757-61. PMID: 11897640. Mercier B et al. Is congenital bilateral absence of vas deferens a primary form of cystic fibrosis? Analyses of the CFTR gene in 67 patients. Am J Hum Genet. 1995; 56(1):272-7. PMID: 7529962. Parad R et al. Diagnostic dilemmas resulting from the immunoreactive trypsinogen/DNA cystic fibrosis newborn screening algorithm. J Pediatr. 2005; 147(3 Suppl):S78-82. PMID: 16202789. 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. PMID: 23974870. Steiner B et al. Common CFTR haplotypes and susceptibility to chronic pancreatitis and congenital bilateral absence of the vas deferens. Hum Mutat. 2011; 32(8):912-20. PMID: 21520337. Strandvik B et al. Spectrum of mutations in the CFTR gene of patients with classical and atypical forms of cystic fibrosis from southwestern Sweden: identification of 12 novel mutations. Genet Test. 2001; 5(3):235-42. PMID: 11788090. Wilschanski M et al. Correlation of sweat chloride concentration with classes of the cystic fibrosis transmembrane conductance regulator gene mutations. J Pediatr. 1995; 127(5):705-10. PMID: 7472820. Wong L et al. The necessity of complete CFTR mutational analysis of an infertile couple before in vitro fertilization. Fertil Steril. 2004; 82(4):947-9. PMID: 15482777. Zielenski J et al. CFTR gene variant for patients with congenital absence of vas deferens. Am J Hum Genet. 1995; 57(4):958-60. PMID: 7573058. -
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	Clinical Genetics and Genomics, Karolinska University Hospital	Jul 31, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Sep 16, 2024	PP3, PM2_moderate -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 06, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jul 20, 2023	The CFTR c.349C>T (p.Arg117Cys) variant has been reported in the published literature in compound heterozygous individuals with classic CF (PMIDs: 31523618 (2019), 24586523 (2014), 21783433 (2011), 11788090 (2001), 7525450 (1994)), and CFTR-related disorders (PMIDs: 28801929 (2017), 22658665 (2012), 21520337 (2011), 7529962 (1995)). In addition, functional studies indicate this variant has deleterious effects on CFTR protein processing and chloride channel conductance (PMIDs: 23891399 (2014), 23974870 (2013), 20932301 (2010)). The frequency of this variant in the general population, 0.0015 (38/26094 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, this variant is classified as pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

CFTR-related disorder

Pathogenic:3

Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, The Hospital for Sick Children	Jun 18, 2019	- -
Pathogenic, no assertion criteria provided	clinical testing	PreventionGenetics, part of Exact Sciences	Dec 20, 2023	The CFTR c.349C>T variant is predicted to result in the amino acid substitution p.Arg117Cys. This variant has previously been reported to be causative for cystic fibrosis and CFTR-related disorders (Dörk et al. 1994. PubMed ID: 7525450; Steiner et al. 2011. PubMed ID: 21520337; Sosnay et al. 2013. PubMed ID: 23974870; Van Goor et al. 2014. PubMed ID: 23891399; www.cftr2.org). This variant is reported in 0.037% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Mar 17, 2017	- -

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

May 28, 2024

- -

Bronchiectasis with or without elevated sweat chloride 1

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Mar 18, 2024

- -

Cystic fibrosis;C5924204:CFTR-related disorder

Pathogenic:1

Pathogenic, criteria provided, single submitter

curation

CFTR-France

Jan 29, 2018

when the variant is in trans with another CF-causing variation, can either result in CF or in a CFTR-RD -

ivacaftor response - Efficacy

Other:1

drug response, reviewed by expert panel

curation

PharmGKB

Mar 24, 2021

PharmGKB Level of Evidence 1A: Level 1A clinical annotations describe variant-drug combinations that have variant-specific prescribing guidance available in a current clinical guideline annotation or an FDA-approved drug label annotation. Annotations of drug labels or clinical guidelines must give prescribing guidance for specific variants (e.g. CYP2C9*3, HLA-B*57:01) or provide mapping from defined allele functions to diplotypes and phenotypes to be used as supporting evidence for a level 1A clinical annotation. Level 1A clinical annotations must also be supported by at least one publication in addition to a clinical guideline or drug label with variant-specific prescribing guidance. Drug-variant association: Efficacy

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.62

BayesDel_addAF

Pathogenic

0.28

BayesDel_noAF

Pathogenic

0.49

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.80

.;D;.;.;T;.

Eigen

Uncertain

0.57

Eigen_PC

Uncertain

0.53

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.95

D;D;D;D;D;D

M_CAP

Pathogenic

0.90

MetaRNN

Pathogenic

0.86

D;D;D;D;D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Uncertain

2.1

.;M;.;.;.;M

PrimateAI

Uncertain

0.59

PROVEAN

Pathogenic

-8.0

D;D;.;.;D;.

REVEL

Pathogenic

0.82

Sift

Pathogenic

0.0

D;D;.;.;D;.

Sift4G

Pathogenic

0.0

D;D;.;.;D;.

Polyphen

1.0

.;D;.;.;.;.

Vest4

0.98

MVP

0.99

MPC

0.015

ClinPred

0.68

GERP RS

5.7

Varity_R

0.74

gMVP

0.94

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

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

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over