NM_000492.4(CFTR):c.2981T>G (p.Phe994Cys) AND Cystic fibrosis

Germline classification:: Uncertain significance (4 submissions)
Last evaluated:: Oct 30, 2021
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:: RCV000577330.7

Allele description [Variation Report for NM_000492.4(CFTR):c.2981T>G (p.Phe994Cys)]

NM_000492.4(CFTR):c.2981T>G (p.Phe994Cys)

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.2981T>G (p.Phe994Cys)

HGVS:

NC_000007.14:g.117606746T>G
NG_016465.4:g.145963T>G
NM_000492.4:c.2981T>GMANE SELECT
NP_000483.3:p.Phe994Cys
NP_000483.3:p.Phe994Cys
LRG_663t1:c.2981T>G
LRG_663:g.145963T>G
LRG_663p1:p.Phe994Cys
NC_000007.13:g.117246800T>G
NM_000492.3:c.2981T>G
NM_000492.4:c.2981T>G

Protein change:

F994C

Links:

dbSNP: rs397508469

NCBI 1000 Genomes Browser:

rs397508469

Molecular consequence:

NM_000492.4:c.2981T>G - 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
SCV000679421	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]
SCV002027477	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]
SCV002202720	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Oct 30, 2021)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 28603918, 28492532
SCV002751404	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Uncertain significance (Sep 8, 2021)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 28603918, 33572515 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	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

Citations

PubMed

Do common in silico tools predict the clinical consequences of amino-acid substitutions in the CFTR gene?

Dorfman R, Nalpathamkalam T, Taylor C, Gonska T, Keenan K, Yuan XW, Corey M, Tsui LC, Zielenski J, Durie P.

Clin Genet. 2010 May;77(5):464-73. doi: 10.1111/j.1399-0004.2009.01351.x. Epub 2009 Jan 6.

PubMed [citation]

PMID:: 20059485

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

See all PubMed Citations (5)

Details of each submission

From ClinVar Staff, National Center for Biotechnology Information (NCBI), SCV000679421.1

#	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 Genome-Nilou Lab, SCV002027477.1

#	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 Invitae, SCV002202720.2

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

Description

This sequence change replaces phenylalanine, which is neutral and non-polar, with cysteine, which is neutral and slightly polar, at codon 994 of the CFTR protein (p.Phe994Cys). This variant is present in population databases (rs397508469, gnomAD 0.0009%). This missense change has been observed in individual(s) with cystic fibrosis (PMID: 28603918). ClinVar contains an entry for this variant (Variation ID: 53612). 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

From Ambry Genetics, SCV002751404.2

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

Description

The p.F994C variant (also known as c.2981T>G), located in coding exon 18 of the CFTR gene, results from a T to G substitution at nucleotide position 2981. The phenylalanine at codon 994 is replaced by cysteine, an amino acid with highly dissimilar properties. This variant was reported in conjunction with (TG)12-5T in an individual in the CFTR-France database who was diagnosed with congenital bilateral absence of vas deferens (CBAVD) however phase information was limited (Claustres M et al. Hum. Mutat., 2017 10;38:1297-1315). This variant has also been identified in newborn screening cohort (Bozdogan ST et al. Genes (Basel), 2021 01;12:). This amino acid position is well 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

Last Updated: May 19, 2024

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