NM_000492.4(CFTR):c.266A>G (p.Tyr89Cys) AND Cystic fibrosis

Germline classification:: Uncertain significance (4 submissions)
Last evaluated:: Feb 14, 2024
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:: RCV000577135.15

Allele description [Variation Report for NM_000492.4(CFTR):c.266A>G (p.Tyr89Cys)]

NM_000492.4(CFTR):c.266A>G (p.Tyr89Cys)

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.266A>G (p.Tyr89Cys)

HGVS:

NC_000007.14:g.117509135A>G
NG_016465.4:g.48352A>G
NG_062452.1:g.773A>G
NM_000492.4:c.266A>GMANE SELECT
NP_000483.3:p.Tyr89Cys
NP_000483.3:p.Tyr89Cys
LRG_663t1:c.266A>G
LRG_663:g.48352A>G
LRG_663p1:p.Tyr89Cys
NC_000007.13:g.117149189A>G
NM_000492.3:c.266A>G

Protein change:

Y89C

Links:

dbSNP: rs397508418

NCBI 1000 Genomes Browser:

rs397508418

Molecular consequence:

NM_000492.4:c.266A>G - 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
SCV000679412	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]
SCV002741290	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Uncertain significance (Feb 14, 2024)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 10790225, 18306312 Citation Link,
SCV003505122	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Jul 14, 2022)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 10790225, 17272608, 26098992, 28492532
SCV004024550	Johns Hopkins Genomics, Johns Hopkins University	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Jul 14, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 17272608, 18306312, 25741868

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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

Citations

PubMed

A novel missense mutation (Y89C) in exon 3 of the CFTR (ABCC7) gene in a young male.

Padoan R, Costantini D, Russo MC, Ambrosioni A, Fiori S, Prandoni S, Cantù-Rajnoldi A, Seia M, Giunta A.

Hum Mutat. 2000 May;15(5):486. No abstract available.

PubMed [citation]

PMID:: 10790225

Utility of a very high IRT/No mutation referral category in cystic fibrosis newborn screening.

Kay DM, Langfelder-Schwind E, DeCelie-Germana J, Sharp JK, Maloney B, Tavakoli NP, Saavedra-Matiz CA, Krein LM, Caggana M, Kier C; New York State Cystic Fibrosis Newborn Screening Consortium..

Pediatr Pulmonol. 2015 Aug;50(8):771-80. doi: 10.1002/ppul.23222. Epub 2015 Jun 22.

PubMed [citation]

PMID:: 26098992

See all PubMed Citations (6)

Details of each submission

From ClinVar Staff, National Center for Biotechnology Information (NCBI), SCV000679412.1

#	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, SCV002741290.2

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

Description

The p.Y89C variant (also known as c.266A>G), located in coding exon 3 of the CFTR gene, results from an A to G substitution at nucleotide position 266. The tyrosine at codon 89 is replaced by cysteine, an amino acid with highly dissimilar properties. This variant was detected as heterozygous in in a male patient with chronic lung infection due to pseudomonas, diffuse bronchiectasis, pancreatic sufficiency, oligospermia, and multiple normal sweat tests; no second alteration was identified (Padoan R et al. Hum Mutat, 2000 May;15:486). Functional studies show that Y89C alteration had a glycosylation pattern and a subcellular distribution comparable to wild-type CFTR, but may still impact channel gating; however, the clinical significance of these findings is unclear (Gené GG et al. Hum Mutat, 2008 May;29:738-49). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, 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 Labcorp Genetics (formerly Invitae), Labcorp, SCV003505122.1

#	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 tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 89 of the CFTR protein (p.Tyr89Cys). This variant is present in population databases (rs397508418, gnomAD 0.003%). This missense change has been observed in individual(s) with clinical features of CFTR-related conditions (PMID: 10790225, 17272608, 26098992). ClinVar contains an entry for this variant (Variation ID: 53541). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. 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 Johns Hopkins Genomics, Johns Hopkins University, SCV004024550.2

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

Description

This CFTR missense variant (rs397508418) is rare (<0.1%) in a large population dataset (gnomADv2.1.1: 2/250722 total alleles; 0.0008%; no homozygotes) and has been reported in ClinVar (Variation ID:53541). It has not been reported in the literature in individuals with features of cystic fibrosis who have a second CF-causing variant, to our knowledge. Two bioinformatic tools queried predict that this substitution would be damaging and a single functional study suggests that this variant may impact CFTR gating. The tyrosine residue at this position is evolutionarily conserved across all species assessed except one. We consider the clinical significance of CFTR c.266A>G to be uncertain at this time.

#	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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