Submissions for variant NM_000492.4(CFTR):c.1705T>G (p.Tyr569Asp)

gnomAD frequency: 0.00010  dbSNP: rs397508276

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
CFTR2	RCV000046434	SCV000245991	pathogenic	Cystic fibrosis	2017-03-17	reviewed by expert panel	research
Counsyl	RCV000046434	SCV000486887	pathogenic	Cystic fibrosis	2016-08-29	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000780130	SCV000917174	pathogenic	not specified	2018-02-08	criteria provided, single submitter	clinical testing	Variant summary: CFTR c.1705T>G (p.Tyr569Asp) results in a non-conservative amino acid change located in the ABC transporter-like of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 9.9e-05 in 120772 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in CFTR causing Cystic Fibrosis (9.9e-05 vs 0.013), allowing no conclusion about variant significance. c.1705T>G has been reported in the literature in multiple individuals affected with Cystic Fibrosis, including families where the variant segregates with disease in the homozygous state (Malone_1998). Multiple functional studies have shown the variant to result in absent chloride transport/conductance (Van Goor_2014, Sosnay_2013). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics	RCV001004268	SCV001163144	pathogenic	Cystic fibrosis; Congenital bilateral aplasia of vas deferens from CFTR mutation		criteria provided, single submitter	clinical testing
CFTR-France	RCV000046434	SCV001169398	pathogenic	Cystic fibrosis	2015-07-03	criteria provided, single submitter	curation
Centogene AG - the Rare Disease Company	RCV000046434	SCV001424388	pathogenic	Cystic fibrosis		criteria provided, single submitter	clinical testing
Clinical Genetics and Genomics, Karolinska University Hospital	RCV001269564	SCV001449639	pathogenic	not provided	2016-04-08	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000046434	SCV001580875	pathogenic	Cystic fibrosis	2024-01-22	criteria provided, single submitter	clinical testing	This sequence change replaces tyrosine, which is neutral and polar, with aspartic acid, which is acidic and polar, at codon 569 of the CFTR protein (p.Tyr569Asp). This variant is present in population databases (rs397508276, gnomAD 0.08%). This missense change has been observed in individual(s) with CFTR-related conditions (PMID: 9482579, 12007216, 12357328, 23613805, 26708955, 27625827). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 53352). 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%. Experimental studies have shown that this missense change affects CFTR function (PMID: 23891399). For these reasons, this variant has been classified as Pathogenic.
Neuberg Centre For Genomic Medicine, NCGM	RCV000046434	SCV002073134	pathogenic	Cystic fibrosis		criteria provided, single submitter	clinical testing	The missense variant p.Y569D in CFTR (NM_000492.4) causes the same amino acid change as a previously established pathogenic variant. This variant has been observed in individuals affected with CFTR-related conditions (Deepak et al, 2012; Schrijver et al, 2017). This variant is present in population databases (rs397508276, ExAC 0.07%). 9 variants within 6 amino acid positions of the variant p.Y569D have been shown to be pathogenic, while none have been shown to be benign. The p.Y569D missense variant is predicted to be damaging by both SIFT and PolyPhen2. The tyrosine residue at codon 569 of CFTR is conserved in all mammalian species. The nucleotide c.1705 in CFTR is predicted conserved by GERP++ and PhyloP across 100 vertebrates. This variant has been reported to affect CFTR protein function. For these reasons, this variant has been classified as Pathogenic.
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV000046434	SCV002507353	pathogenic	Cystic fibrosis	2020-06-25	criteria provided, single submitter	clinical testing
Arcensus	RCV000046434	SCV002564618	likely pathogenic	Cystic fibrosis	2013-02-01	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003473464	SCV004213575	pathogenic	Bronchiectasis with or without elevated sweat chloride 1	2024-03-20	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV001826622	SCV002080656	pathogenic	CFTR-related disorder	2017-09-01	no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV001826622	SCV002507437	pathogenic	CFTR-related disorder	2020-06-25	no assertion criteria provided	clinical testing