NM_000492.4(CFTR):c.2770G>A (p.Asp924Asn) AND Cystic fibrosis

Germline classification:: Uncertain significance (6 submissions)
Last evaluated:: Dec 20, 2019
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:: RCV000577296.17

Allele description [Variation Report for NM_000492.4(CFTR):c.2770G>A (p.Asp924Asn)]

NM_000492.4(CFTR):c.2770G>A (p.Asp924Asn)

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.2770G>A (p.Asp924Asn)

HGVS:

NC_000007.14:g.117603644G>A
NG_016465.4:g.142861G>A
NM_000492.4:c.2770G>AMANE SELECT
NP_000483.3:p.Asp924Asn
NP_000483.3:p.Asp924Asn
LRG_663t1:c.2770G>A
LRG_663:g.142861G>A
LRG_663p1:p.Asp924Asn
NC_000007.13:g.117243698G>A
NM_000492.3:c.2770G>A

Protein change:

D924N

Links:

dbSNP: rs201759207

NCBI 1000 Genomes Browser:

rs201759207

Molecular consequence:

NM_000492.4:c.2770G>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
SCV000679359	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]
SCV000796009	Counsyl	criteria provided, single submitter (Counsyl Autosomal Recessive and X-Linked Classification Criteria (2018))	Uncertain significance (Nov 27, 2017)	unknown	clinical testing	PubMed (2) [See all records that cite these PMIDs] 17331079, 24586523 Citation Link,
SCV001177512	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Uncertain significance (Jan 13, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 17331079, 20562583, 24586523, 29271547 Citation Link,
SCV001981589	CFTR2	reviewed by expert panel (Submitter's publication and website)	Uncertain significance (Dec 20, 2019)	germline	research	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV002573911	Institute of Human Genetics, University of Leipzig Medical Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Sep 5, 2022)	unknown	curation	PubMed (1) [See all records that cite this PMID]
SCV003242236	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Jan 29, 2024)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 20562583, 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
not provided	unknown	yes	1	not provided	not provided	not provided	not provided	curation
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Spectrum of mutations in the CFTR gene in cystic fibrosis patients of Spanish ancestry.

Alonso MJ, Heine-Suñer D, Calvo M, Rosell J, Giménez J, Ramos MD, Telleria JJ, Palacio A, Estivill X, Casals T.

Ann Hum Genet. 2007 Mar;71(Pt 2):194-201.

PubMed [citation]

PMID:: 17331079

CFTR mutations spectrum and the efficiency of molecular diagnostics in Polish cystic fibrosis patients.

Ziętkiewicz E, Rutkiewicz E, Pogorzelski A, Klimek B, Voelkel K, Witt M.

PLoS One. 2014;9(2):e89094. doi: 10.1371/journal.pone.0089094. Erratum in: PLoS One. 2014;9(8):e105738.

PubMed [citation]

PMID:: 24586523
PMCID:: PMC3935850

See all PubMed Citations (7)

Details of each submission

From ClinVar Staff, National Center for Biotechnology Information (NCBI), SCV000679359.1

#	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, SCV000796009.1

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

#	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 Ambry Genetics, SCV001177512.5

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

Description

The p.D924N variant (also known as c.2770G>A), located in coding exon 17 of the CFTR gene, results from a G to A substitution at nucleotide position 2770. The aspartic acid at codon 924 is replaced by asparagine, an amino acid with highly similar properties. This variant was detected in two individuals with cystic fibrosis; however, additional genotype and phenotype information was not provided (Alonso MJ et al. Ann. Hum. Genet., 2007 Mar;71:194-201; Zitkiewicz E et al. PLoS ONE, 2014 Feb;9:e89094). In one French individual, the p.D924N variant was reported in cis with p.F508del (Baatallah N et al. Hum. Mutat., 2018 Apr;39:506-514). This variant was also identified in trans a 5T variant in an individual with recurrent pancreatitis (Koyano S et al. Pancreas, 2010 Jul;39:686-7). This amino acid position is conserved through reptiles. In addition, the in silico prediction for this alteration is inconclusive. Based on available evidence to date, 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 CFTR2, SCV001981589.1

#	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 Institute of Human Genetics, University of Leipzig Medical Center, SCV002573911.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	curation	PubMed (1)

Description

This variant was identified in 1 patient with a clinically confirmed diagnosis of cystic fibrosis. The variant was classified in the context of a project re-classifying variants in the German Cystic Fibrosis Registry (Muko.e.V.). Link: https://www.muko.info/angebote/qualitaetsmanagement/register/cf-einrichtungen/mukoweb. Criteria applied: PM3_STR, PM2_SUP, PM5_SUP, PP3, PS3_SUP, PP4

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	yes	not provided	not provided	not provided		1	not provided	not provided	not provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV003242236.2

#	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 aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 924 of the CFTR protein (p.Asp924Asn). This variant is present in population databases (rs201759207, gnomAD 0.01%). This missense change has been observed in individual(s) with CFTR-related conditions (PMID: 20562583). ClinVar contains an entry for this variant (Variation ID: 53565). 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 with a positive predictive value of 80%. 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

Last Updated: Nov 3, 2024

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