Submissions for variant NM_000492.4(CFTR):c.260T>C (p.Phe87Ser)

gnomAD frequency: 0.00001  dbSNP: rs1310658028

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001216825	SCV001388638	uncertain significance	Cystic fibrosis	2022-11-01	criteria provided, single submitter	clinical testing	This sequence change replaces phenylalanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 87 of the CFTR protein (p.Phe87Ser). This variant is present in population databases (no rsID available, gnomAD 0.007%). This variant has not been reported in the literature in individuals affected with CFTR-related conditions. ClinVar contains an entry for this variant (Variation ID: 946044). 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. This variant disrupts the p.Phe87 amino acid residue in CFTR. Other variant(s) that disrupt this residue have been observed in individuals with CFTR-related conditions (PMID: 8081395, 19181743), which suggests that this may be a clinically significant amino acid residue. 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.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001812256	SCV001472861	uncertain significance	not provided	2020-08-20	criteria provided, single submitter	clinical testing	The CFTR c.260T>C; p.Phe87Ser variant (rs1310658028), to our knowledge, is not reported in the medical literature but is reported in the cystic fibrosis mutation database (see link). This variant is only observed on one allele in the Genome Aggregation Database, indicating it is not a common polymorphism. The phenylalanine at codon 87 is weakly conserved, and computational analyses (SIFT: damaging, PolyPhen-2: benign) predict conflicting effects of this variant on protein structure/function. Additionally, other variants at this codon (c.259T>C; p.Phe87Leu, c.259T>A; p.Phe87Ile) have been reported in individuals with cystic fibrosis or congenital absence of vas deferens (Bienvenu 1994, Sharma 2009, see link to cystic fibrosis mutation database), but the p.Phe87Ile variant was shown in vitro to have no effect on protein function compared to wild type (Sharma 2015). Due to limited information, the clinical significance of the p.Phe87Ser variant is uncertain at this time. References: Link to cystic fibrosis mutation database: http://www.genet.sickkids.on.ca/ Bienvenu T et al. A missense mutation (F87L) in exon 3 of the cystic fibrosis transmembrane conductance regulator gene. Hum Mutat. 1994;3(4):395-396. Sharma N et al. Heterogenous spectrum of CFTR gene mutations in Indian patients with congenital absence of vas deferens. Hum Reprod. 2009;24(5):1229-1236. Sharma H et al. Function, pharmacological correction and maturation of new Indian CFTR gene mutations. J Cyst Fibros. 2015;14(1):34-41.
Genome-Nilou Lab	RCV001216825	SCV002027338	uncertain significance	Cystic fibrosis	2021-09-05	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV001216825	SCV002745557	uncertain significance	Cystic fibrosis	2017-09-15	criteria provided, single submitter	clinical testing	The p.F87S variant (also known as c.260T>C), located in coding exon 3 of the CFTR gene, results from a T to C substitution at nucleotide position 260. The phenylalanine at codon 87 is replaced by serine, an amino acid with highly dissimilar properties. This amino acid position is poorly 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003331082	SCV004038399	uncertain significance	not specified	2023-08-08	criteria provided, single submitter	clinical testing	Variant summary: CFTR c.260T>C (p.Phe87Ser) results in a non-conservative amino acid change located in the ABC transporter type 1, transmembrane domain (IPR011527) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250824 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.260T>C in individuals affected with Cystic Fibrosis and no experimental evidence demonstrating its impact on protein function have been reported. Five submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Natera, Inc.	RCV001833884	SCV002080099	uncertain significance	CFTR-related disorders	2019-01-09	no assertion criteria provided	clinical testing