NM_000492.4(CFTR):c.1040G>C (p.Arg347Pro) AND not provided

Germline classification:: Pathogenic (6 submissions)
Last evaluated:: Jan 23, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV001530124.22

Allele description [Variation Report for NM_000492.4(CFTR):c.1040G>C (p.Arg347Pro)]

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]

Observations:

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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DNA mismatch repair protein Msh2 isoform 4 [Homo sapiens]
DNA mismatch repair protein Msh2 isoform 4 [Homo sapiens]
gi|2240436722|ref|NP_001393561.1|

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000603032	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2021)	Pathogenic (Dec 6, 2021)	germline	clinical testing	Citation Link,
SCV001744798	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen - VKGL Data-share Consensus	no assertion criteria provided	Pathogenic	germline	clinical testing
SCV001956542	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ - VKGL Data-share Consensus See additional submitters Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	no assertion criteria provided	Likely pathogenic	germline	clinical testing
SCV001971843	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center - VKGL Data-share Consensus See additional submitters Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	no assertion criteria provided	Pathogenic	germline	clinical testing
SCV002046175	Quest Diagnostics Nichols Institute San Juan Capistrano	criteria provided, single submitter (Quest Diagnostics criteria)	Pathogenic (Jan 18, 2021)	unknown	clinical testing	PubMed (13) [See all records that cite these PMIDs] 23974870, 20448091, 23891399, 31523618, 22658665, 32429104, 24440181, 18456578, 19885835, 21679131, 15371902, 12767731, 26467025
SCV005046896	Mayo Clinic Laboratories, Mayo Clinic	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jan 23, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link

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Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	2	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Defining the disease liability of variants in the cystic fibrosis transmembrane conductance regulator gene.

Sosnay PR, Siklosi KR, Van Goor F, Kaniecki K, Yu H, Sharma N, Ramalho AS, Amaral MD, Dorfman R, Zielenski J, Masica DL, Karchin R, Millen L, Thomas PJ, Patrinos GP, Corey M, Lewis MH, Rommens JM, Castellani C, Penland CM, Cutting GR.

Nat Genet. 2013 Oct;45(10):1160-7. doi: 10.1038/ng.2745. Epub 2013 Aug 25.

PubMed [citation]

PMID:: 23974870
PMCID:: PMC3874936

Effects of gender and age at diagnosis on disease progression in long-term survivors of cystic fibrosis.

Nick JA, Chacon CS, Brayshaw SJ, Jones MC, Barboa CM, St Clair CG, Young RL, Nichols DP, Janssen JS, Huitt GA, Iseman MD, Daley CL, Taylor-Cousar JL, Accurso FJ, Saavedra MT, Sontag MK.

Am J Respir Crit Care Med. 2010 Sep 1;182(5):614-26. doi: 10.1164/rccm.201001-0092OC. Epub 2010 May 6.

PubMed [citation]

PMID:: 20448091
PMCID:: PMC2937235

See all PubMed Citations (14)

Details of each submission

From ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories, SCV000603032.5

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

Description

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.

#	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 Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen - VKGL Data-share Consensus, SCV001744798.3

#	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	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ - VKGL Data-share Consensus, SCV001956542.1

#	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	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center - VKGL Data-share Consensus, SCV001971843.1

#	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	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Quest Diagnostics Nichols Institute San Juan Capistrano, SCV002046175.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (13)

Description

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.

#	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 Mayo Clinic Laboratories, Mayo Clinic, SCV005046896.1

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

#	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		2	not provided	not provided	not provided

Last Updated: Nov 10, 2024

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Relating variation to medicine