NM_000492.4(CFTR):c.859A>T (p.Asn287Tyr) AND Cystic fibrosis

Germline classification:: Conflicting interpretations of pathogenicity (7 submissions)
Last evaluated:: Nov 13, 2023
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:: RCV000577376.10

Allele description [Variation Report for NM_000492.4(CFTR):c.859A>T (p.Asn287Tyr)]

NM_000492.4(CFTR):c.859A>T (p.Asn287Tyr)

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.859A>T (p.Asn287Tyr)

HGVS:

NC_000007.14:g.117536663A>T
NG_016465.4:g.75880A>T
NM_000492.4:c.859A>TMANE SELECT
NP_000483.3:p.Asn287Tyr
NP_000483.3:p.Asn287Tyr
LRG_663t1:c.859A>T
LRG_663:g.75880A>T
LRG_663p1:p.Asn287Tyr
NC_000007.13:g.117176717A>T
NM_000492.3:c.859A>T
P13569:p.Asn287Tyr

Protein change:

N287Y

Links:

UniProtKB: P13569#VAR_000140; dbSNP: rs397508804

NCBI 1000 Genomes Browser:

rs397508804

Molecular consequence:

NM_000492.4:c.859A>T - 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
SCV000679177	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]
SCV000788445	Counsyl	criteria provided, single submitter (Counsyl Autosomal Recessive and X-Linked Classification Criteria (2018))	Uncertain significance (Mar 15, 2017)	unknown	clinical testing	PubMed (2) [See all records that cite these PMIDs] 9401006, 12529365 Citation Link,
SCV001454033	Natera, Inc.	no assertion criteria provided	Uncertain significance (Sep 16, 2020)	germline	clinical testing
SCV001822024	Genome-Nilou Lab	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Jul 22, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002307517	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Nov 14, 2021)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 9401006, 12529365, 28492532
SCV002574061	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]
SCV002679925	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Uncertain significance (Nov 13, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 12529365, 17539902, 9401006 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	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
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

The p.Arg258Gly mutation in intracellular loop 2 of CFTR is associated with CFTR-related disorders.

Masvidal L, Giménez J, Ramos MD, Domingo C, Farré A, Bassas L, Casals T.

Genet Test Mol Biomarkers. 2009 Dec;13(6):765-8. doi: 10.1089/gtmb.2009.0070.

PubMed [citation]

PMID:: 19810821

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

See all PubMed Citations (6)

Details of each submission

From ClinVar Staff, National Center for Biotechnology Information (NCBI), SCV000679177.1

#	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, SCV000788445.1

#	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 Natera, Inc., SCV001454033.1

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

#	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, SCV001822024.1

#	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, SCV002307517.2

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

Description

This sequence change replaces asparagine, which is neutral and polar, with tyrosine, which is neutral and polar, at codon 287 of the CFTR protein (p.Asn287Tyr). This variant is present in population databases (rs397508804, gnomAD 0.003%). This missense change has been observed in individual(s) with cystic fibrosis (PMID: 9401006). ClinVar contains an entry for this variant (Variation ID: 54069). 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"). Experimental studies have shown that this missense change affects CFTR function (PMID: 12529365). 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 Institute of Human Genetics, University of Leipzig Medical Center, SCV002574061.1

#	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: PS3_MOD, PM2_SUP, PM3, PP3

#	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 Ambry Genetics, SCV002679925.2

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

Description

The p.N287Y variant (also known as c.859A>T), located in coding exon 7 of the CFTR gene, results from an A to T substitution at nucleotide position 859. The asparagine at codon 287 is replaced by tyrosine, an amino acid with dissimilar properties. This alteration was identified with Delta F508 in an individual with a clinical diagnosis of cystic fibrosis (Shrimpton AE et al. Hum Mutat, 1997;10:436-42). In vitro studies showed CFTR protein harboring N287Y has normal maturation, cell surface targeting, and channel gating. However, this variant increased internalization of the protein, leading to reduced expression on the cell surface (Silvis MR et al. J Biol Chem, 2003 Mar;278:11554-60). Additionally, this alteration was identified in an individual diagnosed with idiopathic chronic pancreatitis (Chang MC et al. Clin Genet, 2007 Jun;71:530-9). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. 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: Jun 23, 2024

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