Submissions for variant NM_000492.4(CFTR):c.1721C>A (p.Pro574His)

gnomAD frequency: 0.00001  dbSNP: rs121908758

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
CFTR2	RCV000007539	SCV000924269	pathogenic	Cystic fibrosis	2017-12-08	reviewed by expert panel	research
Baylor Genetics	RCV001004269	SCV001163145	likely pathogenic	Cystic fibrosis; Congenital bilateral aplasia of vas deferens from CFTR mutation		criteria provided, single submitter	clinical testing
CFTR-France	RCV001009367	SCV001169220	pathogenic	Cystic fibrosis; CFTR-related disorder	2018-03-09	criteria provided, single submitter	curation	when the variant is in trans with another CF-causing variation, can either result in CF or in a CFTR-RD
Myriad Genetics, Inc.	RCV000007539	SCV001194016	likely pathogenic	Cystic fibrosis	2019-12-16	criteria provided, single submitter	clinical testing	NM_000492.3(CFTR):c.1721C>A(P574H) is classified as likely pathogenic in the context of cystic fibrosis. Sources cited for classification include the following: PMID 16132229, 20059485, 12815607, 10362539, 7534226, 10923036 and 754013. Classification of NM_000492.3(CFTR):c.1721C>A(P574H) is based on the following criteria: This variant has been observed more frequently in patients with clinical diagnoses and is very rare or not present in genetic databases of healthy individuals. Please note: this variant was assessed in the context of healthy population screening.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000007539	SCV001583409	pathogenic	Cystic fibrosis	2023-07-21	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects CFTR function (PMID: 21594800, 29805046). 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. ClinVar contains an entry for this variant (Variation ID: 7119). This missense change has been observed in individuals with cystic fibrosis and congenital bilateral absence of vas deferens (PMID: 2236053, 9239681, 10923036). This variant is present in population databases (rs121908758, gnomAD 0.002%). This sequence change replaces proline, which is neutral and non-polar, with histidine, which is basic and polar, at codon 574 of the CFTR protein (p.Pro574His).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000007539	SCV001737734	pathogenic	Cystic fibrosis	2021-06-11	criteria provided, single submitter	clinical testing	Variant summary: CFTR c.1721C>A (p.Pro574His) results in a non-conservative amino acid change located in the ABC transporter-like (IPR003439) 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 8e-06 in 250350 control chromosomes. c.1721C>A has been reported in compound heterozygosity with another pathogenic variant in multiple individuals affected with Cystic Fibrosis in the literature (e.g. Kerem_1990, McCague_2019, Dadgostar_2021). These data indicate that the variant is very likely to be associated with disease. Several publications report experimental evidence evaluating an impact on protein function (e.g. Champigny_1995, Cai_2011, Raraigh_2018, Han_2018). The most pronounced variant effect results in <10% of normal CFTR activity. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories cited the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Mayo Clinic Laboratories, Mayo Clinic	RCV002254259	SCV002525774	pathogenic	not provided	2021-09-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000007539	SCV002714188	likely pathogenic	Cystic fibrosis	2019-09-11	criteria provided, single submitter	clinical testing	The p.P574H variant (also known as c.1721C>A), located in coding exon 13 of the CFTR gene, results from a C to A substitution at nucleotide position 1721. The proline at codon 574 is replaced by histidine, an amino acid with similar properties. This variant was reported in three individuals with cystic fibrosis and pancreatic sufficiency in conjunction with p.F508del; full gene sequence and deletion/duplication analyses of CFTR were not performed (Kerem BS et al. Proc. Natl. Acad. Sci. U.S.A., 1990 Nov;87:8447-51; Kristidis P et al. Am. J. Hum. Genet., 1992 Jun;50:1178-84). In functional studies, this variant resulted in an overall decrease in chloride channel activity and to produce less mature glycosylated protein (Champigny G et al. EMBO J., 1995 Jun;14:2417-23; Sheppard DN et al. EMBO J., 1995 Mar;14:876-83; Raraigh KS et al. Am. J. Hum. Genet., 2018 06;102:1062-1077). 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 majority of available evidence to date, this variant is likely to be pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV002490333	SCV002786550	likely pathogenic	Bronchiectasis with or without elevated sweat chloride 1; Cystic fibrosis; Hereditary pancreatitis; Congenital bilateral aplasia of vas deferens from CFTR mutation	2022-01-24	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003473008	SCV004213518	pathogenic	Bronchiectasis with or without elevated sweat chloride 1	2024-02-27	criteria provided, single submitter	clinical testing
OMIM	RCV000007539	SCV000027740	pathogenic	Cystic fibrosis	1990-11-01	no assertion criteria provided	literature only
Natera, Inc.	RCV001831523	SCV002080661	pathogenic	CFTR-related disorder	2017-03-17	no assertion criteria provided	clinical testing
Baylor Genetics	RCV000007539	SCV002583260	pathogenic	Cystic fibrosis		no assertion criteria provided	clinical testing