NM_000492.4(CFTR):c.223C>T (p.Arg75Ter) AND Cystic fibrosis

Germline classification:: Pathogenic (10 submissions)
Last evaluated:: Mar 17, 2017
Review status:: 3 stars out of maximum of 4 stars
reviewed by expert panel

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:: RCV000056362.33

Allele description [Variation Report for NM_000492.4(CFTR):c.223C>T (p.Arg75Ter)]

NM_000492.4(CFTR):c.223C>T (p.Arg75Ter)

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.223C>T (p.Arg75Ter)

Other names:

p.Arg75*

HGVS:

NC_000007.14:g.117509092C>T
NG_016465.4:g.48309C>T
NG_062452.1:g.730C>T
NM_000492.4:c.223C>TMANE SELECT
NP_000483.3:p.Arg75Ter
NP_000483.3:p.Arg75Ter
LRG_663t1:c.223C>T
LRG_663:g.48309C>T
LRG_663p1:p.Arg75Ter
NC_000007.13:g.117149146C>T
NM_000492.3:c.223C>T
p.Arg75X

Protein change:

R75*

Links:

Genetic Testing Registry (GTR): GTR000074114; dbSNP: rs121908749

NCBI 1000 Genomes Browser:

rs121908749

Molecular consequence:

NM_000492.4:c.223C>T - nonsense - [Sequence Ontology: SO:0001587]

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
SCV000071554	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,
SCV001169536	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]
SCV001194207	Myriad Genetics, Inc.	criteria provided, single submitter (Myriad Women's Health Autosomal Recessive and X-Linked Classification Criteria (2019))	Pathogenic (Dec 9, 2019)	unknown	clinical testing	PubMed (6) [See all records that cite these PMIDs] 7541274, 23420618, 7525450, 9806422, 22658665, 23974870 Citation Link,
SCV001587414	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 21, 2024)	germline	clinical testing	PubMed (14) [See all records that cite these PMIDs] 1695717, 7691345, 9725922, 7525450, 10923036, 18456578, 22658665, 22975760, 23276700, 23523379, 23974870, 26014425, 26574590, 28492532
SCV001711952	Johns Hopkins Genomics, Johns Hopkins University	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (May 25, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002507351	Genome Diagnostics Laboratory, The Hospital for Sick Children	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Feb 25, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002564622	Arcensus	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Feb 1, 2013)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002727956	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Pathogenic (Oct 26, 2021)	germline	clinical testing	Citation Link,
SCV004806960	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 26, 2024)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV005042894	Neuberg Centre For Genomic Medicine, NCGM	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Help

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, research, curation
not provided	germline	unknown	not provided	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

CFTR-France, a national relational patient database for sharing genetic and phenotypic data associated with rare CFTR variants.

Claustres M, Thèze C, des Georges M, Baux D, Girodon E, Bienvenu T, Audrezet MP, Dugueperoux I, Férec C, Lalau G, Pagin A, Kitzis A, Thoreau V, Gaston V, Bieth E, Malinge MC, Reboul MP, Fergelot P, Lemonnier L, Mekki C, Fanen P, Bergougnoux A, et al.

Hum Mutat. 2017 Oct;38(10):1297-1315. doi: 10.1002/humu.23276. Epub 2017 Jun 28.

PubMed [citation]

PMID:: 28603918

Transcript analysis of CFTR nonsense mutations in lymphocytes and nasal epithelial cells from cystic fibrosis patients.

Will K, Dörk T, Stuhrmann M, von der Hardt H, Ellemunter H, Tümmler B, Schmidtke J.

Hum Mutat. 1995;5(3):210-20.

PubMed [citation]

PMID:: 7541274

See all PubMed Citations (19)

Details of each submission

From CFTR2 - CFTR2, SCV000071554.4

#	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 CFTR-France, SCV001169536.1

#	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., SCV001194207.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

NM_000492.3(CFTR):c.223C>T(R75*) is classified as pathogenic in the context of cystic fibrosis and is associated with classic disease. Sources cited for classification include the following: PMID 7541274, 23420618, 7525450, 9806422, 22658665 and 23974870. Classification of NM_000492.3(CFTR):c.223C>T(R75*) is based on the following criteria: The variant causes a premature termination codon that is expected to be targeted by nonsense-mediated mRNA decay and is reported in individuals with the relevant phenotype. 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 Labcorp Genetics (formerly Invitae), Labcorp, SCV001587414.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (14)

Description

This sequence change creates a premature translational stop signal (p.Arg75*) in the CFTR gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CFTR are known to be pathogenic (PMID: 1695717, 7691345, 9725922). This variant is present in population databases (rs121908749, gnomAD 0.009%). This premature translational stop signal has been observed in individual(s) with CF and cystic fibrosis (CF) (PMID: 7525450, 10923036, 18456578, 22658665, 22975760, 23276700, 23523379, 23974870, 26014425, 26574590). 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: 48672). 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 Johns Hopkins Genomics, Johns Hopkins University, SCV001711952.1

#	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 Genome Diagnostics Laboratory, The Hospital for Sick Children, SCV002507351.1

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

From Arcensus, SCV002564622.1

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

From Ambry Genetics, SCV002727956.2

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

Description

The p.R75* pathogenic mutation (also known as c.223C>T), located in coding exon 3 of the CFTR gene, results from a C to T substitution at nucleotide position 223. This changes the amino acid at codon 75 from arginine to a stop codon. This mutation was first described in a pancreatic insufficient German individual who was confirmed to have p.N1303K in trans (Dork T et al. Hum Genet. 1994;94(5):533-542). This mutation has pan-ethnic distribution (Rohlfs EM et al. Clin Chem. 2011;57(6):841-8) and is associated with elevated sweat chloride levels and pancreatic insufficiency (Sosnay PR et al. Nat Genet. 2013;45(10):1160-1167). This variant has been reported in multiple individuals with an elevated sweat chloride level in The Clinical and Functional TRanslation of CFTR (CFTR2) database (available at http://cftr2.org. Accessed 10/25/2021). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, 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

From Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center, SCV004806960.1

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

From Neuberg Centre For Genomic Medicine, NCGM, SCV005042894.1

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

Description

The stop-gained variant c.223C>T p.Arg75Ter in the CFTR gene has been reported in the hemizygous and heterozygous state in multiple individuals affected with Cystic Fibrosis Guo et al., 2021; Singh et al., 2015. This variant is reported with the allele frequency 0.0007% in the gnomAD Exomes and novel not in any individuals in 1000 Genomes. It has been submitted to ClinVar as Likely Pathogenic/ Pathogenic Multiple Submissions. This variant is predicted to cause a loss of normal protein function through protein truncation. Loss of function variants has been previously reported to be disease-causing. 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	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Oct 26, 2024

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