NM_000492.4(CFTR):c.3294G>C (p.Trp1098Cys) AND Cystic fibrosis

Germline classification:: Pathogenic (4 submissions)
Last evaluated:: Aug 31, 2018
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:: RCV000576929.14

Allele description [Variation Report for NM_000492.4(CFTR):c.3294G>C (p.Trp1098Cys)]

NM_000492.4(CFTR):c.3294G>C (p.Trp1098Cys)

Genes:

CFTR:CF transmembrane conductance regulator [Gene - OMIM - HGNC]
LOC111674472:DNase I hypersensitive sites in introns 16 and 17a of CFTR [Gene]

Variant type:

single nucleotide variant

Cytogenetic location:

7q31.2

Genomic location:

Preferred name:

NM_000492.4(CFTR):c.3294G>C (p.Trp1098Cys)

HGVS:

NC_000007.14:g.117611735G>C
NG_016465.4:g.150952G>C
NG_056128.2:g.4789G>C
NM_000492.4:c.3294G>CMANE SELECT
NP_000483.3:p.Trp1098Cys
NP_000483.3:p.Trp1098Cys
LRG_663t1:c.3294G>C
LRG_663:g.150952G>C
LRG_663p1:p.Trp1098Cys
NC_000007.13:g.117251789G>C
NM_000492.3:c.3294G>C

Protein change:

W1098C

Links:

dbSNP: rs397508533

NCBI 1000 Genomes Browser:

rs397508533

Molecular consequence:

NM_000492.4:c.3294G>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
SCV000679374	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]
SCV000924219	CFTR2	reviewed by expert panel (Sosnay PR et al. (Nat Genet 2013))	Pathogenic (Aug 31, 2018)	germline	research	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV001360603	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Feb 26, 2024)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 14998948, 10798368, 16963320, 21416780, 30046002, 32596391, 22103471 Citation Link,
SCV004517274	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (May 30, 2023)	germline	clinical testing	PubMed (9) [See all records that cite these PMIDs] 7537150, 8662892, 10798368, 14998948, 16963320, 21416780, 30046002, 32227567, 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	research, literature only
not provided	germline	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

Characterization of Ancestral Origin of Cystic Fibrosis of Patients with New Reported Mutations in CFTR.

Paz-Y-Miño C, Zambrano AK, Ruiz-Cabezas JC, Armendáriz-Castillo I, García-Cárdenas JM, Guerrero S, López-Cortés A, Pérez-Villa A, Guevara-Ramírez P, Yumiceba V, Leone PE.

Biomed Res Int. 2020;2020:9074760. doi: 10.1155/2020/9074760.

PubMed [citation]

PMID:: 32596391
PMCID:: PMC7288203

See all PubMed Citations (12)

Details of each submission

From ClinVar Staff, National Center for Biotechnology Information (NCBI), SCV000679374.1

#	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 CFTR2, SCV000924219.1

#	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, SCV001360603.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (7)

Description

Variant summary: CFTR c.3294G>C (p.Trp1098Cys) results in a non-conservative amino acid change located in the ABC transporter type 1, transmembrane domain (IPR011527) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251088 control chromosomes. This variant has also been reported without the specification of the nucleotide level designation and a non-informative genotype (second allele not specified) in individuals with Cystic Fibrosis, and CBAVD (example, Perez_2007, Chavez-Saldana_2010, Saldana-Alvarez_2012). Additionally two different variants, namely, c.3294G>T (p.Trp1098Cys), and c.3292T>C (p.Trp1098Arg) have been classified internally classified on the pathogenic spectrum. Sick kids and the CFTR-France databases have reports of presumably the same patient, namely a newborn presenting with pulmonary symptoms, positive IRT, mildly elevated sweat chloride levels and p.F508del in trans. An additional study lists its presence (without nucleotide level specification) in cis with the 5T allele in an individual with CBAVD reportedly homozygous for the 5T allele (Danziger_2004). At least one publication reports experimental evidence evaluating an impact on protein function in-vitro (Han_2018). The most pronounced variant effect results in approximately 3.4% of normal residual CFTR function. The following publications have been ascertained in the context of this evaluation (PMID: 14998948, 10798368, 16963320, 21416780, 30046002, 32596391, 22103471). ClinVar contains an entry for this variant (Variation ID: 53709). Based on the evidence outlined above, the variant was 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 Labcorp Genetics (formerly Invitae), Labcorp, SCV004517274.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (9)

Description

This variant disrupts the p.Trp1098 amino acid residue in CFTR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7537150, 8662892). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. 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. ClinVar contains an entry for this variant (Variation ID: 53709). This missense change has been observed in individual(s) with cystic fibrosis (PMID: 10798368, 14998948, 16963320, 21416780, 30046002, 32227567). This variant is present in population databases (rs397508533, gnomAD 0.006%). This sequence change replaces tryptophan, which is neutral and slightly polar, with cysteine, which is neutral and slightly polar, at codon 1098 of the CFTR protein (p.Trp1098Cys).

#	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: Oct 13, 2024

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