NM_000492.4(CFTR):c.1040G>C (p.Arg347Pro) AND Cystic fibrosis

This record was updated by the submitter. Please see the current version.

Germline classification:: Pathogenic (11 submissions)
Last evaluated:: Mar 3, 2004
Review status:: 4 stars out of maximum of 4 stars
practice guideline

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000007530.32

Allele description

NM_000492.4(CFTR):c.1040G>C (p.Arg347Pro)

Gene:

CFTR:CF transmembrane conductance regulator [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

7q31.2

Genomic location:

Preferred name:

NM_000492.4(CFTR):c.1040G>C (p.Arg347Pro)

HGVS:

NC_000007.14:g.117540270G>C
NG_016465.4:g.79487G>C
NM_000492.4:c.1040G>CMANE SELECT
NP_000483.3:p.Arg347Pro
NP_000483.3:p.Arg347Pro
LRG_663t1:c.1040G>C
LRG_663:g.79487G>C
LRG_663p1:p.Arg347Pro
NC_000007.13:g.117180324G>C
NM_000492.3:c.1040G>C
P13569:p.Arg347Pro

Protein change:

R347P; ARG347PRO

Links:

Genetic Testing Registry (GTR): GTR000074114; Genetic Testing Registry (GTR): GTR000257096; Genetic Testing Registry (GTR): GTR000500233; UniProtKB: P13569#VAR_000155; OMIM: 602421.0006; dbSNP: rs77932196

NCBI 1000 Genomes Browser:

rs77932196

Molecular consequence:

NM_000492.4:c.1040G>C - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Cystic fibrosis (CF)
Synonyms:: Mucoviscidosis
Identifiers:: MONDO: MONDO:0009061; MedGen: C0010674; Orphanet: 586; OMIM: 219700

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000027731	OMIM	no assertion criteria provided	Pathogenic (Jan 1, 1991)	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV000071389	American College of Medical Genetics and Genomics (ACMG) - The ACMG recommended carrier screening panel	practice guideline (Guideline for cystic fibrosis carrier screening)	pathogenic (Mar 3, 2004)	germline	curation	PubMed (1) [See all records that cite this PMID]
SCV000071521	CFTR2 - CFTR2	reviewed by expert panel (Sosnay PR et al. (Nat Genet 2013))	Pathogenic (Mar 17, 2017)	germline	research	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV000696817	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Jan 27, 2017)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] LabCorp Variant Classification Summary - May 2015.docx, Citation Link,
SCV000886258	Mendelics	criteria provided, single submitter (Mendelics Assertion Criteria 2017)	Pathogenic (Nov 5, 2018)	unknown	clinical testing	Citation Link,
SCV001169458	CFTR-France	criteria provided, single submitter (Claustres M et al. (Hum Mutat 2017))	Pathogenic (Jan 29, 2018)	germline	curation	PubMed (1) [See all records that cite this PMID]
SCV001194235	Myriad Genetics, Inc.	criteria provided, single submitter (Myriad Women's Health Autosomal Recessive and X-Linked Classification Criteria (2019))	Pathogenic (Dec 20, 2019)	unknown	clinical testing	PubMed (4) [See all records that cite these PMIDs] 12454843, 23974870, 8535440, 20448091 Citation Link,
SCV001425443	Johns Hopkins Genomics, Johns Hopkins University	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Feb 27, 2020)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001588862	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Dec 16, 2023)	germline	clinical testing	PubMed (8) [See all records that cite these PMIDs] 1723032, 2344617, 10376575, 12400067, 31523618, 23891399, 23974870, 28492532
SCV001622786	GeneReviews	no classification provided	not provided	unknown	literature only	PubMed (2) [See all records that cite these PMIDs] 15371902, 20301428
SCV002699407	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Pathogenic (Dec 27, 2021)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 16275171, 23974870 Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only
not provided	unknown	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	research, curation
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing, curation
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing, literature only

Citations

PubMed

Hereditary disorders in Saguenay-Lac-St-Jean (Quebec, Canada).

De Braekeleer M.

Hum Hered. 1991;41(3):141-6.

PubMed [citation]

PMID:: 1937486

Laboratory standards and guidelines for population-based cystic fibrosis carrier screening.

Grody WW, Cutting GR, Klinger KW, Richards CS, Watson MS, Desnick RJ; Subcommittee on Cystic Fibrosis Screening, Accreditation of Genetic Services Committee, ACMG. American College of Medical Genetics..

Genet Med. 2001 Mar-Apr;3(2):149-54. No abstract available.

PubMed [citation]

PMID:: 11280952

See all PubMed Citations (19)

PMC

Cystic fibrosis population carrier screening: 2004 revision of American College of Medical Genetics mutation panel.

Watson MS, Cutting GR, Desnick RJ, Driscoll DA, Klinger K, Mennuti M, Palomaki GE, Popovich BW, Pratt VM, Rohlfs EM, Strom CM, Richards CS, Witt DR, Grody WW.

Genetics in Medicine. 2004 Sep-Oct; 6(5): 387-391

PMC [article]

PMCID:: PMC3110945
PMID:: 15371902
DOI:: 10.1097/01.GIM.0000139506.11694.7C

Details of each submission

From OMIM, SCV000027731.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (1)

Description

In 3 sibs with cystic fibrosis (CF; 219700) from a family identified as UT 1446, Dean et al. (1990) found a C-to-G transversion at position 1172 in the CFTR gene, resulting in substitution of proline for aspartic acid (R347P). The mutation destroyed a HhaI restriction site and created a NcoI site.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From American College of Medical Genetics and Genomics (ACMG) - The ACMG recommended carrier screening panel, SCV000071389.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	PubMed (1)

Description

Converted during submission to Pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From CFTR2 - CFTR2, SCV000071521.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	research	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000696817.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

Description

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."

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Mendelics, SCV000886258.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From CFTR-France, SCV001169458.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Myriad Genetics, Inc., SCV001194235.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Johns Hopkins Genomics, Johns Hopkins University, SCV001425443.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

Description

Disease-causing CFTR variant. See www.CFTR2.org for phenotype information.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Invitae, SCV001588862.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (8)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From GeneReviews, SCV001622786.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (2)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Ambry Genetics, SCV002699407.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 16, 2024

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