NM_000492.4(CFTR):c.889C>T (p.Arg297Trp) AND Cystic fibrosis

Germline classification:: Uncertain significance (5 submissions)
Last evaluated:: Jun 30, 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:: RCV000577784.10

Allele description [Variation Report for NM_000492.4(CFTR):c.889C>T (p.Arg297Trp)]

NM_000492.4(CFTR):c.889C>T (p.Arg297Trp)

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.889C>T (p.Arg297Trp)

HGVS:

NC_000007.14:g.117540119C>T
NG_016465.4:g.79336C>T
NM_000492.4:c.889C>TMANE SELECT
NP_000483.3:p.Arg297Trp
NP_000483.3:p.Arg297Trp
LRG_663t1:c.889C>T
LRG_663:g.79336C>T
LRG_663p1:p.Arg297Trp
NC_000007.13:g.117180173C>T
NM_000492.3:c.889C>T
NM_000492.4:c.889C>T

Protein change:

R297W

Links:

dbSNP: rs397508814

NCBI 1000 Genomes Browser:

rs397508814

Molecular consequence:

NM_000492.4:c.889C>T - 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
SCV000679511	ClinVar Staff, National Center for Biotechnology Information (NCBI)	no classification provided	not provided	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV000788779	Counsyl	criteria provided, single submitter (Counsyl Autosomal Recessive and X-Linked Classification Criteria (2018))	Uncertain significance (Dec 15, 2016)	unknown	clinical testing	Citation Link,
SCV002027375	Genome-Nilou Lab	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Sep 5, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002685537	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Uncertain significance (Jun 30, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 19810821, 22094894, 25087612, 9272157 Citation Link,
SCV003451946	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Sep 6, 2022)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 9272157, 22094894, 28492532

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	literature only
not provided	germline	no	not provided	not provided	not provided	not provided	not provided	clinical testing
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

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

The p.Arg258Gly mutation in intracellular loop 2 of CFTR is associated with CFTR-related disorders.

Masvidal L, Giménez J, Ramos MD, Domingo C, Farré A, Bassas L, Casals T.

Genet Test Mol Biomarkers. 2009 Dec;13(6):765-8. doi: 10.1089/gtmb.2009.0070.

PubMed [citation]

PMID:: 19810821

See all PubMed Citations (6)

Details of each submission

From ClinVar Staff, National Center for Biotechnology Information (NCBI), SCV000679511.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	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 Counsyl, SCV000788779.1

#	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	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Genome-Nilou Lab, SCV002027375.1

#	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	no	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Ambry Genetics, SCV002685537.3

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

Description

The p.R297W variant (also known as c.889C>T), located in coding exon 8 of the CFTR gene, results from a C to T substitution at nucleotide position 889. The arginine at codon 297 is replaced by tryptophan, an amino acid with dissimilar properties. This variant was described in an individual with congenital bilateral absence of the vas deferens, who reportedly had additional CFTR variants detected, including the 5T allele in trans and homozygous p.Q1352H alleles (Dörk T et al. Hum Genet, 1997 Sep;100:365-77). This variant was also detected in a pediatric chronic pancreatitis cohort in one case who was heterozygous for this variant with no additional variants reported (Sultan M et al. J Pediatr Gastroenterol Nutr, 2012 May;54:645-50). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

#	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 Labcorp Genetics (formerly Invitae), Labcorp, SCV003451946.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 297 of the CFTR protein (p.Arg297Trp). This variant is present in population databases (rs397508814, gnomAD 0.03%). This missense change has been observed in individual(s) with chronic or recurrent pancreatitis and congenital absence of the vas deferens (PMID: 9272157, 22094894). ClinVar contains an entry for this variant (Variation ID: 54080). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

#	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 29, 2024

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