NM_000492.4(CFTR):c.2981T>G (p.Phe994Cys) AND not specified

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Mar 29, 2019
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:: RCV000855590.9

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)

Synonyms:: AllHighlyPenetrant
Identifiers:: MedGen: CN169374

Recent activity

Clear Turn Off Turn On

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

Help

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000696940	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Uncertain significance (Mar 29, 2019)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 20059485, 25735457, 28603918 Citation Link,
SCV001158155	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process)	Uncertain significance (Jan 28, 2019)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000696940

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Uncertain significance
(Mar 29, 2019)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

Citation Link,

SCV001158155

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

criteria provided, single submitter

(ARUP Molecular Germline Variant Investigation Process)

Uncertain significance
(Jan 28, 2019)

germline

clinical testing

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
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

Comparative ex vivo, in vitro and in silico analyses of a CFTR splicing mutation: Importance of functional studies to establish disease liability of mutations.

Ramalho AS, Clarke LA, Sousa M, Felicio V, Barreto C, Lopes C, Amaral MD.

J Cyst Fibros. 2016 Jan;15(1):21-33. doi: 10.1016/j.jcf.2015.02.002. Epub 2015 Feb 27.

PubMed [citation]

PMID:: 25735457

See all PubMed Citations (3)

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000696940.2

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

Description

Variant summary: CFTR c.2981T>G (p.Phe994Cys) results in a non-conservative amino acid change located in the 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 4.1e-06 in 245896 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. The variant of interest has been reported in the literature and in multiple databases in a male patient affected with Congenital Bilateral Absence of the Vas Deferens (CBAVD) who carried a severe disease variant (likely deltaF508) on the other allele (Dorfman 2010, Claustres 2017); however this patient also carried a mild pathogenic variant (TG12T5) in cis, which could explain his phenotype. These reports therefore do not provide unequivocal conclusions about association of the variant with Cystic Fibrosis. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as 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 ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories, SCV001158155.1

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

Description

The CFTR c.2981T>G; p.Phe994Cys variant (rs397508469) is reported in an individual with congenital bilateral absence of the vas deferens (CBAVD) who also carries 5T on the same allele and F508del on the other allele (see database link). This variant is reported as uncertain in ClinVar (Variation ID: 53612). This variant is only observed on one allele in the Genome Aggregation Database, indicating it is not a common polymorphism. The phenylalanine at codon 994 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. However, given the lack of clinical and functional data, the significance of this variant is uncertain at this time. REFERENCES Link to SickKids database: http://www.genet.sickkids.on.ca/cftr/MutationDetailPage.external?sp=797

#	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: Apr 1, 2023

ClinVar

Relating variation to medicine