NM_000492.4(CFTR):c.2173G>A (p.Glu725Lys) AND Cystic fibrosis

Germline classification:: Conflicting interpretations of pathogenicity (4 submissions)
Last evaluated:: Sep 28, 2022
Review status:: criteria provided, conflicting classifications

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:: RCV000577536.17

Allele description [Variation Report for NM_000492.4(CFTR):c.2173G>A (p.Glu725Lys)]

NM_000492.4(CFTR):c.2173G>A (p.Glu725Lys)

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.2173G>A (p.Glu725Lys)

HGVS:

NC_000007.14:g.117592340G>A
NG_016465.4:g.131557G>A
NM_000492.4:c.2173G>AMANE SELECT
NP_000483.3:p.Glu725Lys
NP_000483.3:p.Glu725Lys
LRG_663t1:c.2173G>A
LRG_663:g.131557G>A
LRG_663p1:p.Glu725Lys
NC_000007.13:g.117232394G>A
NM_000492.3:c.2173G>A

Protein change:

E725K

Links:

dbSNP: rs199791061

NCBI 1000 Genomes Browser:

rs199791061

Molecular consequence:

NM_000492.4:c.2173G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Cystic fibrosis (CF)
Synonyms:: Mucoviscidosis
Identifiers:: MONDO: MONDO:0009061; MedGen: C0010674; Orphanet: 586; OMIM: 219700

Recent activity

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pyruvate decarboxylase 4-like [Raphanus sativus]
pyruvate decarboxylase 4-like [Raphanus sativus]
gi|1072983400|ref|XP_018442241.1|

Protein

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000678980	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]
SCV001175411	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Uncertain significance (Apr 29, 2022)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 12752573, 15698946, 16128988, 17719933, 18306312, 28603918, 30420730 Citation Link,
SCV001495828	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Sep 28, 2022)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 12752573, 15698946, 18306312, 28492532
SCV001822096	Genome-Nilou Lab	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Jul 22, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

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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	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	no	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Molecular evaluation of CFTR sequence variants in male infertility of testicular origin.

Larriba S, Bonache S, Sarquella J, Ramos MD, Giménez J, Bassas L, Casals T.

Int J Androl. 2005 Oct;28(5):284-90.

PubMed [citation]

PMID:: 16128988

Primary sclerosing cholangitis in childhood is associated with abnormalities in cystic fibrosis-mediated chloride channel function.

Pall H, Zielenski J, Jonas MM, DaSilva DA, Potvin KM, Yuan XW, Huang Q, Freedman SD.

J Pediatr. 2007 Sep;151(3):255-9. Epub 2007 Jul 24.

PubMed [citation]

PMID:: 17719933

See all PubMed Citations (9)

Details of each submission

From ClinVar Staff, National Center for Biotechnology Information (NCBI), SCV000678980.1

#	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 Ambry Genetics, SCV001175411.4

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

Description

The p.E725K variant (also known as c.2173G>A), located in coding exon 14 of the CFTR gene, results from a G to A substitution at nucleotide position 2173. The glutamic acid at codon 725 is replaced by lysine, an amino acid with similar properties. This variant has been detected in individuals with cystic fibrosis (des Georges M et al. J. Cyst. Fibros., 2004 Dec;3:265-72, Claustres M et al. Hum Mutat, 2017 10;38:1297-1315, Kanavakis E et al. Clin Genet, 2003 May;63:400-9). In addition, the alteration has been reported in patients with idiopathic chronic pancreatitis, primary sclerosing cholangitis, suboptimal fertility, and hypertrypsinemia (Zou WB et al. Clin Transl Gastroenterol, 2018 11;9:204, Pall H et al. J Pediatr, 2007 Sep;151:255-9, Larriba S et al. Int J Androl, 2005 Oct;28:284-90, Gené GG et al. Hum Mutat, 2008 May;29:738-49).). This amino acid position is not 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

From Invitae, SCV001495828.2

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

Description

This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 725 of the CFTR protein (p.Glu725Lys). This variant is present in population databases (rs199791061, gnomAD 0.02%). This missense change has been observed in individual(s) with cystic fibrosis (PMID: 12752573, 15698946, 18306312). ClinVar contains an entry for this variant (Variation ID: 53448). 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 not expected to disrupt CFTR protein function. 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 Genome-Nilou Lab, SCV001822096.1

#	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

Last Updated: Sep 16, 2024

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