VCV000007141.21 - ClinVar

NM_000492.4(CFTR):c.2551C>T (p.Arg851Ter)

Germline

Reviewed by expert panel

Reviewed by expert panel. Learn more about how ClinVar calculates review status.

Pathogenic

for Cystic fibrosis

Classification is based on the expert panel submission

Mar 2017 by CFTR2

The classification is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000492.4(CFTR):c.2551C>T (p.Arg851Ter)

Variation ID: 7141 Accession: VCV000007141.21

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 7q31.2 7: 117594990 (GRCh38) [ NCBI UCSC ] 7: 117235044 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Mar 29, 2015	Apr 13, 2025	Mar 17, 2017

HGVS

Nucleotide	Protein	Molecular consequence
NM_000492.4:c.2551C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000483.3:p.Arg851Ter	nonsense
NC_000007.14:g.117594990C>T
NC_000007.13:g.117235044C>T
NG_016465.4:g.134207C>T
LRG_663:g.134207C>T
LRG_663t1:c.2551C>T	LRG_663p1:p.Arg851Ter

... more HGVS ... less HGVS

Protein change

R851*

Other names

Canonical SPDI

NC_000007.14:117594989:C:T

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

Trans-Omics for Precision Medicine (TOPMed) 0.00000

Exome Aggregation Consortium (ExAC) 0.00001

Links

ClinGen: CA340645 OMIM: 602421.0036 dbSNP: rs121909012 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
CFTR		Gene associated with autosomal recessive phenotype	Not yet evaluated	GRCh38 GRCh37	4081	5549

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Cystic fibrosis	Pathogenic (9)	reviewed by expert panel	Mar 17, 2017	RCV000007561.24
Congenital bilateral aplasia of vas deferens from CFTR mutation Cystic fibrosis	Pathogenic (1)	criteria provided, single submitter	-	RCV001004481.1
CFTR-related disorder	Pathogenic (1)	no assertion criteria provided	Mar 17, 2017	RCV001831532.1
not provided	Pathogenic (1)	criteria provided, single submitter	Jul 23, 2021	RCV002476942.1
Bronchiectasis with or without elevated sweat chloride 1	Pathogenic (1)	criteria provided, single submitter	Mar 7, 2024	RCV003473019.2

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Pathogenic (Mar 17, 2017) C Contributing to aggregate classification	reviewed by expert panel (Sosnay PR et al. (Nat Genet 2013)) Method: research	Cystic fibrosis Affected status: yes Allele origin: germline	CFTR2 Study: CFTR2 Accession: SCV000071556.4 First in ClinVar: Oct 18, 2013 Last updated: Jan 06, 2018	Other databases https://cftr2.org https://cftr2.org

Likely pathogenic (Nov 24, 2014) N Not contributing to aggregate classification	criteria provided, single submitter (Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015)) Method: literature only	Cystic fibrosis (Autosomal recessive inheritance) Affected status: unknown Allele origin: unknown	Counsyl Accession: SCV000220911.2 First in ClinVar: Mar 29, 2015 Last updated: Dec 24, 2022	Publications: PubMed (12) PubMed: 9439669‚ 1723056‚ 17331079‚ 15181619‚ 15776432‚ 24019231‚ 23065710‚ 23276700‚ 24633926‚ 23687349‚ 19202204‚ 10923036

Pathogenic (Nov 05, 2018) N Not contributing to aggregate classification	criteria provided, single submitter (Mendelics Assertion Criteria 2017) Method: clinical testing	Cystic fibrosis Affected status: yes Allele origin: unknown	Mendelics Accession: SCV000886220.2 First in ClinVar: Apr 12, 2018 Last updated: Dec 11, 2022

Pathogenic (-) N Not contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Congenital bilateral aplasia of vas deferens from CFTR mutation Cystic fibrosis Affected status: unknown Allele origin: germline	Baylor Genetics Accession: SCV001163526.1 First in ClinVar: Mar 01, 2020 Last updated: Mar 01, 2020

Pathogenic (Jan 29, 2018) N Not contributing to aggregate classification	criteria provided, single submitter (Claustres M et al. (Hum Mutat 2017)) Method: curation	cystic fibrosis Affected status: yes Allele origin: germline	CFTR-France Accession: SCV001169496.1 First in ClinVar: Mar 16, 2020 Last updated: Mar 16, 2020	Publications: PubMed (1) PubMed: 28603918

Pathogenic (Jan 12, 2025) N Not contributing to aggregate classification	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Cystic fibrosis Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV001586222.5 First in ClinVar: May 10, 2021 Last updated: Feb 16, 2025	Publications: PubMed (4) PubMed: 1695717‚ 7691345‚ 9725922‚ 22483971 Comment: This sequence change creates a premature translational stop signal (p.Arg851) in the CFTR gene. It is expected to result in an absent or disrupted protein … (more) This sequence change creates a premature translational stop signal (p.Arg851) 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 not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with congenital bilateral absence of vas deferens (PMID: 22483971). ClinVar contains an entry for this variant (Variation ID: 7141). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. (less)

Pathogenic (Jun 16, 2022) N Not contributing to aggregate classification	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	Cystic fibrosis Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV002555916.1 First in ClinVar: Aug 08, 2022 Last updated: Aug 08, 2022	Publications: PubMed (2) PubMed: 23974870‚ 23065710 Comment: Variant summary: CFTR c.2551C>T (p.Arg851X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein … (more) Variant summary: CFTR c.2551C>T (p.Arg851X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 251312 control chromosomes (gnomAD). c.2551C>T has been reported in the literature in multiple individuals affected with Cystic Fibrosis (e.g. Sosnay_2013). These data indicate that the variant is very likely to be associated with disease. Experimental evidence evaluating an impact on protein function demonstrated the variant induced two defects: the generation of a PTC and alternative splicing of exon 15 (Hinzpeter_2012). Five ClinVar submitters including an expert panel (CFTR2) (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)

Pathogenic (Nov 03, 2023) N Not contributing to aggregate classification	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Cystic fibrosis Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV002740658.2 First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024	Publications: PubMed (5) PubMed: 1723056‚ 23065710‚ 23276700‚ 23974870‚ 28544683 Comment: The p.R851* pathogenic mutation (also known as c.2551C>T), located in coding exon 15 of the CFTR gene, results from a C to T substitution at … (more) The p.R851* pathogenic mutation (also known as c.2551C>T), located in coding exon 15 of the CFTR gene, results from a C to T substitution at nucleotide position 2551. This changes the amino acid from an arginine to a stop codon within coding exon 15. This mutation was reported in a child with severe cystic fibrosis (White MB et al. Genomics, 1991 Nov;11:778-9) and was identified cystic fibrosis cohorts (Kenková P et al. J. Cyst. Fibros., 2013 Sep;12:532-7; Soltysova A et al. Clin Respir J, 2018 Mar;12:1197-1206). This mutation is associated with elevated sweat chloride levels, pancreatic insufficiency, and a higher rate of Pseudomonas infection (Sosnay PR et al. Nat. Genet., 2013 Oct;45:1160-7). One study suggests that in addition to nonsense mediated decay, the pathogenicity of this mutation is related to an increase in exon 15 skipping (Hinzpeter A et al. Hum. Mutat., 2013 Feb;34:287-91). 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. (less)

Pathogenic (Jul 23, 2021) N Not contributing to aggregate classification	criteria provided, single submitter (Quest Diagnostics criteria) Method: clinical testing	not provided Affected status: unknown Allele origin: unknown	Quest Diagnostics Nichols Institute San Juan Capistrano Accession: SCV002774337.1 First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022	Publications: PubMed (14) PubMed: 1723056‚ 28603918‚ 23276700‚ 19202204‚ 17331079‚ 24633926‚ 23687349‚ 23065710‚ 22483971‚ 15776432‚ 10923036‚ 9439669‚ 23974870‚ 31036917 Comment: This nonsense variant causes the premature termination of CFTR protein synthesis. In addition, it has been reported in individuals affected with Cystic Fibrosis and Congenital … (more) This nonsense variant causes the premature termination of CFTR protein synthesis. In addition, it has been reported in individuals affected with Cystic Fibrosis and Congenital Bilateral Absence of the Vas Deferens (CBAVD) in the published literature (PMID: 9439669 (1997), 28603918 (2017), 23974870 (2013), 22483971 (2012), 19202204 (2008), 17331079 (2007), 10923036 (2000)). In addition, this variant has been shown to result in exon 15 skipping (PMID: 23065710 (2013)). Based on the available information, this variant is classified as pathogenic. (less)

Pathogenic (Mar 07, 2024) N Not contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Bronchiectasis with or without elevated sweat chloride 1 Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV004213422.2 First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024

Pathogenic (Nov 01, 1991) N Not contributing to aggregate classification	no assertion criteria provided Method: literature only	CYSTIC FIBROSIS Affected status: not provided Allele origin: germline	OMIM Accession: SCV000027762.2 First in ClinVar: Apr 04, 2013 Last updated: Apr 12, 2018	Publications: PubMed (1) PubMed: 1723056 Comment on evidence: In a compound heterozygote with cystic fibrosis (CF; 219700), White et al. (1991) found a de novo mutation which converted codon 851 (CGA;ARG) to a … (more) In a compound heterozygote with cystic fibrosis (CF; 219700), White et al. (1991) found a de novo mutation which converted codon 851 (CGA;ARG) to a stop codon (TGA). The mother lacked any CFTR mutation and the father was heterozygous for the common delta-F508 mutation. (less)

Pathogenic (Mar 17, 2017) N Not contributing to aggregate classification	no assertion criteria provided Method: clinical testing	CFTR-related disorders Affected status: unknown Allele origin: germline	Natera, Inc. Accession: SCV002080768.1 First in ClinVar: Feb 13, 2022 Last updated: Feb 13, 2022

Pathogenic (Dec 25, 2023) N Not contributing to aggregate classification	no assertion criteria provided Method: clinical testing	Cystic fibrosis Affected status: yes Allele origin: maternal	Department of Urology, First Affiliated Hospital of Nanjing Medical University Accession: SCV004217835.2 First in ClinVar: Jun 29, 2024 Last updated: Apr 13, 2025	Other databases https://cftr2.org https://cftr2.org Number of individuals with the variant: 1 Sex: female Ethnicity/Population group: Asian Testing laboratory: MyGenostics Company (Beijing, China) Date variant was reported to submitter: 2018-10-17

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Comment:

This sequence change creates a premature translational stop signal (p.Arg851*) 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 not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with congenital bilateral absence of vas deferens (PMID: 22483971). ClinVar contains an entry for this variant (Variation ID: 7141). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.

Comment:

Variant summary: CFTR c.2551C>T (p.Arg851X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 251312 control chromosomes (gnomAD). c.2551C>T has been reported in the literature in multiple individuals affected with Cystic Fibrosis (e.g. Sosnay_2013). These data indicate that the variant is very likely to be associated with disease. Experimental evidence evaluating an impact on protein function demonstrated the variant induced two defects: the generation of a PTC and alternative splicing of exon 15 (Hinzpeter_2012). Five ClinVar submitters including an expert panel (CFTR2) (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

Comment:

The p.R851* pathogenic mutation (also known as c.2551C>T), located in coding exon 15 of the CFTR gene, results from a C to T substitution at nucleotide position 2551. This changes the amino acid from an arginine to a stop codon within coding exon 15. This mutation was reported in a child with severe cystic fibrosis (White MB et al. Genomics, 1991 Nov;11:778-9) and was identified cystic fibrosis cohorts (Kenková P et al. J. Cyst. Fibros., 2013 Sep;12:532-7; Soltysova A et al. Clin Respir J, 2018 Mar;12:1197-1206). This mutation is associated with elevated sweat chloride levels, pancreatic insufficiency, and a higher rate of Pseudomonas infection (Sosnay PR et al. Nat. Genet., 2013 Oct;45:1160-7). One study suggests that in addition to nonsense mediated decay, the pathogenicity of this mutation is related to an increase in exon 15 skipping (Hinzpeter A et al. Hum. Mutat., 2013 Feb;34:287-91). 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.

Comment:

This nonsense variant causes the premature termination of CFTR protein synthesis. In addition, it has been reported in individuals affected with Cystic Fibrosis and Congenital Bilateral Absence of the Vas Deferens (CBAVD) in the published literature (PMID: 9439669 (1997), 28603918 (2017), 23974870 (2013), 22483971 (2012), 19202204 (2008), 17331079 (2007), 10923036 (2000)). In addition, this variant has been shown to result in exon 15 skipping (PMID: 23065710 (2013)). Based on the available information, this variant is classified as pathogenic.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Sequencing as a first-line methodology for cystic fibrosis carrier screening.	Beauchamp KA	Genetics in medicine : official journal of the American College of Medical Genetics	2019	PMID: 31036917
Comprehensive genetic study of cystic fibrosis in Slovak patients in 25 years of genetic diagnostics.	Soltysova A	The clinical respiratory journal	2018	PMID: 28544683
CFTR-France, a national relational patient database for sharing genetic and phenotypic data associated with rare CFTR variants.	Claustres M	Human mutation	2017	PMID: 28603918
Identification of a novel 5' alternative CFTR mRNA isoform in a patient with nasal polyposis and CFTR mutations.	Hinzpeter A	Human mutation	2014	PMID: 24633926
Aerobic fitness is associated with lower risk of hospitalization in children with cystic fibrosis.	Pérez M	Pediatric pulmonology	2014	PMID: 24019231
Defining the disease liability of variants in the cystic fibrosis transmembrane conductance regulator gene.	Sosnay PR	Nature genetics	2013	PMID: 23974870
Next generation diagnostics of cystic fibrosis and CFTR-related disorders by targeted multiplex high-coverage resequencing of CFTR.	Trujillano D	Journal of medical genetics	2013	PMID: 23687349
Distribution of CFTR mutations in the Czech population: positive impact of integrated clinical and laboratory expertise, detection of novel/de novo alleles and relevance for related/derived populations.	Křenková P	Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society	2013	PMID: 23276700
Alternative splicing of in-frame exon associated with premature termination codons: implications for readthrough therapies.	Hinzpeter A	Human mutation	2013	PMID: 23065710
Mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) in Chinese patients with congenital bilateral absence of vas deferens.	Li H	Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society	2012	PMID: 22483971
Mutation analysis of the CFTR gene in Slovak cystic fibrosis patients by DHPLC and subsequent sequencing: identification of four novel mutations.	Kolesár P	General physiology and biophysics	2008	PMID: 19202204
Spectrum of mutations in the CFTR gene in cystic fibrosis patients of Spanish ancestry.	Alonso MJ	Annals of human genetics	2007	PMID: 17331079
Misprocessing of the CFTR protein leads to mild cystic fibrosis phenotype.	Clain J	Human mutation	2005	PMID: 15776432
Distal intestinal obstruction syndrome in adults with cystic fibrosis.	Dray X	Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association	2004	PMID: 15181619
Spectrum of CFTR mutations in cystic fibrosis and in congenital absence of the vas deferens in France.	Claustres M	Human mutation	2000	PMID: 10923036
Relation between mutations of the cystic fibrosis gene and idiopathic pancreatitis.	Cohn JA	The New England journal of medicine	1998	PMID: 9725922
High heterogeneity for cystic fibrosis in Spanish families: 75 mutations account for 90% of chromosomes.	Casals T	Human genetics	1997	PMID: 9439669
Molecular basis of defective anion transport in L cells expressing recombinant forms of CFTR.	Yang Y	Human molecular genetics	1993	PMID: 7691345
A de novo cystic fibrosis mutation: CGA (Arg) to TGA (stop) at codon 851 of the CFTR gene.	White MB	Genomics	1991	PMID: 1723056
A cluster of cystic fibrosis mutations in the first nucleotide-binding fold of the cystic fibrosis conductance regulator protein.	Cutting GR	Nature	1990	PMID: 1695717
https://cftr2.org	-	-	-	-
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Text-mined citations for rs121909012 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Apr 13, 2025

ClinVar Genomic variation as it relates to human health

NM_000492.4(CFTR):c.2551C>T (p.Arg851Ter)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs121909012 ...