7-117540270-G-A

Position:

chr7-117540270-G-A

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong

The NM_000492.4(CFTR):c.1040G>A(p.Arg347His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000052 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. R347P) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000053 ( 0 hom. )

Consequence

CFTR
NM_000492.4 missense

Scores

Clinical Significance

Pathogenic reviewed by expert panel P:21

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 18 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-C is described in Lovd as [Pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.988

PP5

Variant 7-117540270-G-A is Pathogenic according to our data. Variant chr7-117540270-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 7182.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr7-117540270-G-A is described in Lovd as [Pathogenic]. Variant chr7-117540270-G-A 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>A	p.Arg347His	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>A	p.Arg347His	missense_variant	8/27	1	NM_000492.4	ENSP00000003084.6		P13569-1

Frequencies

GnomAD3 genomes

AF:

0.0000460

AC:

AN:

152118

Hom.:

Cov.:

show subpopulations

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:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000103

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000239

AC:

AN:

251126

Hom.:

AF XY:

0.0000295

AC XY:

AN XY:

135700

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

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:

0.0000352

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000527

AC:

AN:

1461724

Hom.:

Cov.:

AF XY:

0.0000454

AC XY:

AN XY:

727158

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.0000630

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000460

AC:

AN:

152118

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74316

show subpopulations

Gnomad4 AFR

AF:

0.00

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:

0.000103

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000390

Hom.:

Bravo

AF:

0.0000416

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.00

AC:

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:21

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Cystic fibrosis

Pathogenic:7

Pathogenic, reviewed by expert panel	research	CFTR2	Mar 17, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 14, 2024	The p.R347H pathogenic mutation (also known as c.1040G>A and 1172G>A), located in coding exon 8 of the CFTR gene, results from a G to A substitution at nucleotide position 1040. The arginine at codon 347 is replaced by histidine, an amino acid with highly similar properties. This mutation has been reported in several individuals with CFTR or CFTR-related disorders and is included in the American College of Medical Genetics and Genomics (ACMG)'s list of recommended screening variants (Miller ME et al. J Obstet Gynaecol Can, 2018 Mar). In addition, this mutation has been detected in an individual with mild pulmonary disease and pancreatic sufficiency who carried p.F508del on the other allele (Cremonesi L. et al. Hum Mutat. 1992;1:314-319; Hojo S et al. Clin Genet. 1998;53:50-53). One functional study showed that this mutation results in reduced chloride channel activity but retains normal protein processing capabilities (Clain J et al. J Biol Chem. 2001;276(12):9045-9). Functional in vitro studies conclude that this mutation may be associated with elevated sweat chloride levels and pancreatic insufficiency (Sosnay PR et al. Nat Genet. 2013;45(10):1160-1167). Of note, this mutation has been observed as part of a complex allele with p.D979A (Hojo S et al. Clin Genet. 1998;53:50-53). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Nov 20, 2019	NM_000492.3(CFTR):c.1040G>A(R347H) is classified as pathogenic in the context of cystic fibrosis and is associated with the non-classic form of disease. Sources cited for classification include the following: PMID 23974870. Classification of NM_000492.3(CFTR):c.1040G>A(R347H) 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. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Apr 09, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	Nov 05, 2018	- -
Pathogenic, no assertion criteria provided	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 06, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 17, 2023	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 347 of the CFTR protein (p.Arg347His). This variant is present in population databases (rs77932196, gnomAD 0.004%). This missense change has been observed in individuals 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: 7182). 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%. This variant disrupts the p.Arg347 amino acid residue in CFTR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 2344617, 7683952). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

not provided

Pathogenic:7

Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Aug 15, 2024	The CFTR c.1040G>A (p.Arg347His) variant has been reported in the published literature in individuals with cystic fibrosis (PMID: 1284538 (1992), 15371902 (2004), 19652440 (2009)), Congenital bilateral absence of the vas deferens (CBAVD) (PMID: 22483971 (2012)), and pancreatitis (PMID: 22658665 (2012)). Assessment of experimental evidence suggests this variant results in abnormal protein function (PMID: 23891399 (2014), 23974870 (2013)). The frequency of this variant in the general population, 0.000039 (5/128898 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, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2022	CFTR: PM3:Very Strong, PM2, PM5, PP3 -
Likely pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	May 10, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Apr 06, 2015	- -

CFTR-related disorder

Pathogenic:2

Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	May 20, 2019	- -
Pathogenic, no assertion criteria provided	clinical testing	PreventionGenetics, part of Exact Sciences	Jan 31, 2024	The CFTR c.1040G>A variant is predicted to result in the amino acid substitution p.Arg347His. This variant has been repeatedly documented to cause cystic fibrosis (see, for example, Cremonesi et al. 1992. PubMed ID: 1284538; Sosnay et al. 2013. PubMed ID: 23974870; cftr2.org). This variant is reported in 0.0039% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic. -

not specified

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Aug 09, 2018

The CFTR c.1040G>A; p.Arg347His variant (rs77932196), is reported in the literature in multiple individuals affected with the pancreatic sufficient form of cystic fibrosis (Cremonesi 1992, Gallati 2009, Ooi 2012). The variant has also been reported in a compound heterozygous state in individuals with pancreatic insufficiency (de Gracia 2005, Izumikawa 2009) or congenital bilateral absence of vas deferens (Li 2012, Steiner 2011, Ravnik-Glavac 2000). This variant is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 7182), and is found in the general population with an overall allele frequency of 0.003% (7/276828 alleles) in the Genome Aggregation Database. Additionally, other variants at this codon (c.1040G>C; p.Arg347Pro, c.1040G>T; p.Arg347Leu) have been reported in individuals with cystic fibrosis and are considered pathogenic (Audrezet 2004, Ooi 2012, Sosnay 2013, Van Goor 2014). Functional analyses of the variant protein shows a reduction of chloride transport activity (Anderson 1991, Clain 2001, Sheppard 1993, Smith 2001, Sosnay 2013, Van Goor 2014). The arginine at codon 347 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that the p.Arg347His variant is deleterious. Based on available information, this variant is considered to be moderately pathogenic. References: Anderson MP et al. Demonstration that CFTR is a chloride channel by alteration of its anion selectivity. Science. 1991 Jul 12;253(5016):202-5. Audrezet MP et al. Genomic rearrangements in the CFTR gene: extensive allelic heterogeneity and diverse mutational mechanisms. Hum Mutat. 2004 Apr;23(4):343-57. Clain J et al. Two mild cystic fibrosis-associated mutations result in severe cystic fibrosis when combined in cis and reveal a residue important for cystic fibrosis transmembrane conductance regulator processing and function. J Biol Chem. 2001 Mar 23;276(12):9045-9. Cremonesi L et al. Four new mutations of the CFTR gene (541delC, R347H, R352Q, E585X) detected by DGGE analysis in Italian CF patients, associated with different clinical phenotypes. Hum Mutat. 1992 1(4):314-9. de Gracia J et al. Genotype-phenotype correlation for pulmonary function in cystic fibrosis. Thorax. 2005 Jul;60(7):558-63. Gallati S et al. Cystic fibrosis transmembrane conductance regulator mutations in azoospermic and oligospermic men and their partners. Reprod Biomed Online. 2009 19(5):685-94. Izumikawa K et al. Unique mutations of the cystic fibrosis transmembrane conductance regulator gene of three cases of cystic fibrosis in Nagasaki, Japan. Intern Med. 2009;48(15):1327-31. Li H et al. Mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) in Chinese patients with congenital bilateral absence of vas deferens. J Cyst Fibros. 2012 Jul;11(4):316-23. Ooi C. et al. Cystic fibrosis transmembrane conductance regulator (CFTR) gene mutations in pancreatitis. J Cyst Fibros. 2012 11(5):355-62. Ravnik-Glavac M et al. Study of mutant and polyvariant mutant CFTR genes in patients with congenital absence of the vas deferens. Pflugers Arch. 2000;439(3 Suppl):R53-5. Sheppard DN et al. Mutations in CFTR associated with mild-disease-form Cl- channels with altered pore properties. Nature. 1993 Mar 11;362(6416):160-4. Smith SS et al. CFTR: covalent and noncovalent modification suggests a role for fixed charges in anion conduction. J Gen Physiol. 2001 Oct;118(4):407-31. 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. Steiner B et al. Common CFTR haplotypes and susceptibility to chronic pancreatitis and congenital bilateral absence of the vas deferens. Hum Mutat. 2011 Aug;32(8):912-20. 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. -

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

Mar 13, 2024

- -

Bronchiectasis with or without elevated sweat chloride 1

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Mar 22, 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 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.85

BayesDel_addAF

Pathogenic

0.40

BayesDel_noAF

Pathogenic

0.44

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.89

D;.;.;D;.

Eigen

Pathogenic

0.95

Eigen_PC

Pathogenic

0.91

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.99

D;D;D;D;D

M_CAP

Pathogenic

0.81

MetaRNN

Pathogenic

0.99

D;D;D;D;D

MetaSVM

Pathogenic

0.95

MutationAssessor

Pathogenic

2.9

M;.;.;.;M

PrimateAI

Uncertain

0.73

PROVEAN

Uncertain

-2.4

N;.;.;N;.

REVEL

Pathogenic

0.89

Sift

Uncertain

0.0030

D;.;.;D;.

Sift4G

Pathogenic

0.0

D;.;.;D;.

Polyphen

1.0

D;.;.;.;.

Vest4

0.90

MutPred

0.96

Loss of methylation at R347 (P = 0.0238);Loss of methylation at R347 (P = 0.0238);Loss of methylation at R347 (P = 0.0238);.;Loss of methylation at R347 (P = 0.0238);

MVP

1.0

MPC

0.0079

ClinPred

0.75

GERP RS

5.4

Varity_R

0.89

gMVP

0.95

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