NM_000492.4(CFTR):c.2476G>A (p.Glu826Lys) AND Cystic fibrosis

Germline classification:: Uncertain significance (5 submissions)
Last evaluated:: May 31, 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:: RCV000577037.9

Allele description [Variation Report for NM_000492.4(CFTR):c.2476G>A (p.Glu826Lys)]

NM_000492.4(CFTR):c.2476G>A (p.Glu826Lys)

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.2476G>A (p.Glu826Lys)

HGVS:

NC_000007.14:g.117592643G>A
NG_016465.4:g.131860G>A
NM_000492.4:c.2476G>AMANE SELECT
NP_000483.3:p.Glu826Lys
NP_000483.3:p.Glu826Lys
LRG_663t1:c.2476G>A
LRG_663:g.131860G>A
LRG_663p1:p.Glu826Lys
NC_000007.13:g.117232697G>A
NM_000492.3:c.2476G>A
NM_000492.4:c.2476G>A
P13569:p.Glu826Lys

Protein change:

E826K

Links:

UniProtKB: P13569#VAR_000220; dbSNP: rs397508381

NCBI 1000 Genomes Browser:

rs397508381

Molecular consequence:

NM_000492.4:c.2476G>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

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000678990	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]
SCV000795535	Counsyl	criteria provided, single submitter (Counsyl Autosomal Recessive and X-Linked Classification Criteria (2018))	Uncertain significance (Nov 9, 2017)	unknown	clinical testing	PubMed (3) [See all records that cite these PMIDs] 9736778, 9849891, 27728908 Citation Link,
SCV002027455	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]
SCV002262557	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Oct 4, 2022)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 27728908, 28603918, 9736778, 9849891, 28492532
SCV002738305	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Uncertain significance (May 31, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 9736778, 9849891, 9921909 Citation Link

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

A Clinical and Molecular Survey of 62 Cystic Fibrosis Patients from Umbria (Central Italy) Disclosing a High Frequency (2.4%) of the 2184insA Allele: Implications for Screening.

Prontera P, Isidori I, Mencarini V, Pennoni G, Mencarelli A, Stangoni G, Di Cara G, Verrotti A.

Public Health Genomics. 2016;19(6):336-341. doi: 10.1159/000450849. Epub 2016 Oct 12.

PubMed [citation]

PMID:: 27728908

See all PubMed Citations (7)

Details of each submission

From ClinVar Staff, National Center for Biotechnology Information (NCBI), SCV000678990.1

#	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, SCV000795535.1

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

#	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, SCV002027455.1

#	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 Labcorp Genetics (formerly Invitae), Labcorp, SCV002262557.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 826 of the CFTR protein (p.Glu826Lys). This variant is present in population databases (rs397508381, gnomAD 0.004%). This missense change has been observed in individual(s) with cystic fibrosis (PMID: 27728908, 28603918). ClinVar contains an entry for this variant (Variation ID: 53495). 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. Experimental studies have shown that this missense change affects CFTR function (PMID: 9736778, 9849891). 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, SCV002738305.3

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

Description

The p.E826K variant (also known as c.2476G>A), located in coding exon 14 of the CFTR gene, results from a G to A substitution at nucleotide position 2476. The glutamic acid at codon 826 is replaced by lysine, an amino acid with similar properties. This alteration was detected in heterozygous state in an individual with sarcoidosis, who did not have a second CFTR variant identified (Bombieri C et al. Hum. Genet., 1998 Dec;103:718-22). In vitro studies did not find significant difference between the mutant and wild type (Wei L et al. FEBS Lett., 1998 Nov;439:121-6; Vankeerberghen A et al. Hum. Mol. Genet., 1998 Oct;7:1761-9). 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

Last Updated: Sep 29, 2024

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