Submissions for variant NM_000492.4(CFTR):c.1730A>T (p.Tyr577Phe)

dbSNP: rs397508286

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000577606	SCV000792633	uncertain significance	Cystic fibrosis	2017-07-05	criteria provided, single submitter	clinical testing
Johns Hopkins Genomics, Johns Hopkins University	RCV000577606	SCV001430626	likely benign	Cystic fibrosis	2020-08-03	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001811321	SCV001471990	uncertain significance	not provided	2019-12-23	criteria provided, single submitter	clinical testing	The CFTR c.1730A>T; p.Tyr577Phe variant (rs39750828) is reported in the literature on the same chromosome as the c.1742dupT variant in an individual affected with cystic fibrosis that also carried the common pathogenic p.Phe508del variant (Stuhrmann 1997). While p.Tyr577Phe has also been reported in an individual with infertility without the linked c.1742dupT variant, it is not clear that the detection methods used in this study would have detected both variants (Morea 2005). The p.Tyr577Phe variant is reported on a single chromosome (1/250312 alleles) in the Genome Aggregation Database, indicating it is not a common polymorphism. The tyrosine at codon 577 is moderately conserved and computational analyses (SIFT, PolyPhen-2) predict that this variant is tolerated. Computational analyses (Alamut v.2.11) predict that this variant may impact splicing by creating a novel cryptic acceptor splice site, although RNA analyses would be required to confirm this. Given the lack of clinical and functional data, the significance of the p.Tyr577Phe variant is uncertain at this time. References: Morea A et al. Gender-sensitive association of CFTR gene mutations and 5T allele emerging from a large survey on infertility. Mol Hum Reprod. 2005 Aug;11(8):607-14. Stuhrmann M et al. Detection of 100% of the CFTR mutations in 63 CF families from Tyrol. Clin Genet. 1997 Oct;52(4):240-6.
Genome-Nilou Lab	RCV000577606	SCV001822082	uncertain significance	Cystic fibrosis	2021-07-22	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Leipzig Medical Center	RCV000577606	SCV002574036	uncertain significance	Cystic fibrosis	2022-09-05	criteria provided, single submitter	curation	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: PM2_SUP, PM3_SUP, PP3, BP2, BS3_SUP
Ambry Genetics	RCV000577606	SCV005559942	uncertain significance	Cystic fibrosis	2024-09-17	criteria provided, single submitter	clinical testing	The p.Y577F variant (also known as c.1730A>T), located in coding exon 13 of the CFTR gene, results from an A to T substitution at nucleotide position 1730. The tyrosine at codon 577 is replaced by phenylalanine, an amino acid with highly similar properties. This mutation was reported in an individual with cystic fibrosis and was determined to be in cis with another CFTR variant, both of which were in trans (on different chromosomes) with p.F508del (Stuhrmann M et al. Clin. Genet., 1997 Oct;52:240-6). This amino acid position is not well 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 variant remains unclear.
ClinVar Staff, National Center for Biotechnology Information (NCBI)	RCV000577606	SCV000678926	not provided	Cystic fibrosis		no assertion provided	literature only