7-117540270-G-C

Position:

chr7-117540270-G-C

Variant summary

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

The NM_000492.4(CFTR):c.1040G>C(p.Arg347Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000397 in 1,613,842 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 (★★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R347H) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000042 ( 0 hom. )

Consequence

CFTR
NM_000492.4 missense

Scores

Clinical Significance

Pathogenic practice guideline P:20O:1

Conservation

PhyloP100: 9.42

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 transmembrane_region Helical; Name=6 (size 18) in uniprot entity CFTR_HUMAN there are 9 pathogenic changes around while only 1 benign (90%) 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 chr7-117540270-G-A is described in Lovd as [Pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.887

PP5

Variant 7-117540270-G-C is Pathogenic according to our data. Variant chr7-117540270-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 7110.Status of the report is practice_guideline, 4 stars. Variant chr7-117540270-G-C is described in Lovd as [Pathogenic]. Variant chr7-117540270-G-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CFTR	NM_000492.4 linkuse as main transcript	c.1040G>C	p.Arg347Pro	missense_variant	8/27	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.1040G>C	p.Arg347Pro	missense_variant	8/27	1	NM_000492.4	ENSP00000003084.6		P13569-1

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152118

Hom.:

Cov.:

show subpopulations

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:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000239

AC:

AN:

251126

Hom.:

AF XY:

0.00000737

AC XY:

AN XY:

135700

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:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000529

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000417

AC:

AN:

1461724

Hom.:

Cov.:

AF XY:

0.0000426

AC XY:

AN XY:

727158

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000540

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152118

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74316

show subpopulations

Gnomad4 AFR

AF:

0.0000241

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:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000390

Hom.:

Bravo

AF:

0.0000227

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.000218

EpiControl

AF:

0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:20Other:1

Revision: practice guideline

LINK: link

Submissions by phenotype

Cystic fibrosis

Pathogenic:10Other:1

Pathogenic, practice guideline	curation	American College of Medical Genetics and Genomics (ACMG)	Mar 03, 2004	- -
Pathogenic, criteria provided, single submitter	curation	CFTR-France	Jan 29, 2018	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 1991	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	Nov 05, 2018	- -
not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 16, 2023	This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 347 of the CFTR protein (p.Arg347Pro). This variant is present in population databases (rs77932196, gnomAD 0.005%). This missense change has been observed in individual(s) with cystic fibrosis and congenital absence of the vas deferns (PMID: 1723032, 2344617, 10376575, 12400067, 31523618). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 7110). 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: 23891399, 23974870). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Johns Hopkins Genomics, Johns Hopkins University	Feb 27, 2020	Disease-causing CFTR variant. See www.CFTR2.org for phenotype information. -
Pathogenic, reviewed by expert panel	research	CFTR2	Mar 17, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Dec 27, 2021	The p.R347P pathogenic mutation (also known as c.1040G>C), located in coding exon 8 of the CFTR gene, results from a G to C substitution at nucleotide position 1040. The arginine at codon 347 is replaced by proline, an amino acid with dissimilar properties. This pathogenic mutation has been associated with variable pancreatic sufficiency, variable pulmonary disease, and elevated sweat chloride levels; in addition, functional in vitro studies showed significantly decreased CFTR expression and no chloride conduction (Braun AT et al. J Cyst Fibros. 2006;5(1):33-41; Sosnay PR et al. Nat Genet. 2013;45(10):1160-7). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 27, 2017	Variant summary: The CFTR c.1040G>C (p.Arg347Pro) variant located in the ABC transporter type 1, transmembrane domain (via InterPro) involves the alteration of a conserved nucleotide, which 4/5 in silico tools predict a damaging outcome. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 1/121338, which does not exceed the estimated maximal expected allele frequency of a pathogenic CFTR variant of 1/77. Multiple publications have cited the variant in affected individuals, and multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. The variant of interest is a known, well-established common Pathogenic. Therefore, the variant of interest has been classified as "pathogenic." -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Dec 20, 2019	NM_000492.3(CFTR):c.1040G>C(R347P) is classified as pathogenic in the context of cystic fibrosis. Sources cited for classification include the following: PMID 12454843, 23974870, 8535440 and 20448091. Classification of NM_000492.3(CFTR):c.1040G>C(R347P) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. -

not provided

Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jan 18, 2021	This variant has been reported in individuals affected with Cystic Fibrosis in the published literature (PMID: 15371902 (2004), 32429104 (2020), 31523618 (2019), 22658665 (2012), 20448091 (2010)). Functional studies have shown that this variant results in defective CFTR protein maturation and protein conductance (PMID: 24440181 (2014), 23891399 (2014), 23974870 (2013)). Therefore, the variant is classified as pathogenic. -
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	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Dec 06, 2021	The CFTR c.1040G>C; p.Arg347Pro variant (rs77932196) has been reported in multiple patients diagnosed with cystic fibrosis (Chavez-Saldana 2010, Dean 1990, Ivady 2011) and is associated with both pancreatic-sufficient and -insufficient disease (Dean 1990, Ooi 2012, CFTR2 database). It has also been identified in individuals with congenital bilateral absence of vas deferens and infertility (Amato 2012, Tomaiuolo 2011) when found in-trans with a mildly pathogenic CFTR variant (Tomaiuolo 2011). Functional characterization of the p.Arg347Pro variant protein indicates a failure to generate mature protein, leading to the loss of chloride transport activity (Sosnay 2013, Van Goor 2014). The variant is listed as pathogenic in ClinVar (Variation ID: 7110) and is observed twice in the Exome Variant Server (2/13006 alleles) and 6 times in the Genome Aggregation Database (6/245866 alleles). The arginine at residue 347 is highly conserved (Alamut v2.10), and computational algorithms (Mutation Taster, PolyPhen-2, SIFT) predict that this variant is deleterious. Based on the above information, p.Arg347Pro variant is classified as moderately pathogenic. References: CFTR2 database: https://www.cftr2.org/ Amato F et al. Extensive molecular analysis of patients bearing CFTR-related disorders. J Mol Diagn. 2012; 14(1):81-9. Chavez-Saldana M et al. CFTR allelic heterogeneity in Mexican patients with cystic fibrosis: implications for molecular screening. Rev Invest Clin. 2010; 62(6):546-52. Dean M et al. Multiple mutations in highly conserved residues are found in mildly affected cystic fibrosis patients. Cell. 1990; 61(5):863-70. Ivady G et al. Distribution of CFTR mutations in Eastern Hungarians: relevance to genetic testing and to the introduction of newborn screening for cystic fibrosis. J Cyst Fibros. 2011; 10(3):217-20. 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. Tomaiuolo R et al. Enhanced frequency of CFTR gene variants in couples who are candidates for assisted reproductive technology treatment. Clin Chem Lab Med. 2011; 49(8):1289-93. Van Goor F et al. Effect of ivacaftor on CFTR forms with missense mutations associated with defects in protein processing or function. J Cyst Fibros. 2014; 13(1):29-36. -
Likely 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	Mayo Clinic Laboratories, Mayo Clinic	Jan 23, 2023	- -

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

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

- -

CFTR-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Natera, Inc.

Mar 17, 2017

- -

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 08, 2024

- -

Bronchiectasis with or without elevated sweat chloride 1

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Mar 20, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.35

BayesDel_noAF

Pathogenic

0.42

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.78

D;.;.;D;.

Eigen

Pathogenic

0.95

Eigen_PC

Pathogenic

0.91

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.98

D;D;D;D;D

M_CAP

Pathogenic

0.86

MetaRNN

Pathogenic

0.89

D;D;D;D;D

MetaSVM

Pathogenic

0.90

MutationAssessor

Pathogenic

2.9

M;.;.;.;M

PrimateAI

Uncertain

0.75

PROVEAN

Benign

-0.72

N;.;.;N;.

REVEL

Pathogenic

0.80

Sift

Benign

0.062

T;.;.;T;.

Sift4G

Pathogenic

0.0

D;.;.;D;.

Polyphen

1.0

D;.;.;.;.

Vest4

0.99

MVP

1.0

MPC

0.014

ClinPred

0.79

GERP RS

5.4

Varity_R

0.98

gMVP

0.99

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