Submissions for variant NM_000492.4(CFTR):c.595C>T (p.His199Tyr)

gnomAD frequency: 0.00001  dbSNP: rs121908802

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
CFTR2	RCV000056399	SCV000071504	pathogenic	Cystic fibrosis	2017-03-17	reviewed by expert panel	research
Counsyl	RCV000056399	SCV000487061	likely pathogenic	Cystic fibrosis	2016-09-30	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000056399	SCV000697036	pathogenic	Cystic fibrosis	2017-06-13	criteria provided, single submitter	clinical testing	Variant summary: The CFTR c.595C>T (p.His199Tyr) variant involves the alteration of a conserved nucleotide, resulting in a missense substitution that lies within the ABC transporter type 1, transmembrane domain (InterPro). 4/5 in silico tools predict a damaging outcome for this variant. This variant is absent from the large control database ExAC (0/121410 control chromosomes). The variant has been identified in numerous cystic fibrosis patients. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic/likely pathogenic. Taken together, this variant is classified as pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000755925	SCV000883601	pathogenic	not provided	2017-09-19	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000763155	SCV000893742	pathogenic	Bronchiectasis with or without elevated sweat chloride 1; Cystic fibrosis; Hereditary pancreatitis; Congenital bilateral aplasia of vas deferens from CFTR mutation	2018-10-31	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV001004441	SCV001163486	pathogenic	Cystic fibrosis; Congenital bilateral aplasia of vas deferens from CFTR mutation		criteria provided, single submitter	clinical testing
CFTR-France	RCV000056399	SCV001169307	pathogenic	Cystic fibrosis	2018-01-29	criteria provided, single submitter	curation
Labcorp Genetics (formerly Invitae), Labcorp	RCV000056399	SCV001580660	pathogenic	Cystic fibrosis	2024-12-15	criteria provided, single submitter	clinical testing	This sequence change replaces histidine, which is basic and polar, with tyrosine, which is neutral and polar, at codon 199 of the CFTR protein (p.His199Tyr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with cystic fibrosis (PMID: 7525450, 10798368, 12007216, 15858154, 18456578, 27143075, 28608624). ClinVar contains an entry for this variant (Variation ID: 54018). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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: 23974870). For these reasons, this variant has been classified as Pathogenic.
Johns Hopkins Genomics, Johns Hopkins University	RCV000056399	SCV002570341	pathogenic	Cystic fibrosis	2022-09-07	criteria provided, single submitter	clinical testing	Disease-causing CFTR variant. See www.CFTR2.org for phenotype information.
Ambry Genetics	RCV000056399	SCV002656482	pathogenic	Cystic fibrosis	2023-05-24	criteria provided, single submitter	clinical testing	The p.H199Y pathogenic mutation (also known as c.595C>T), located in coding exon 6 of the CFTR gene, results from a C to T substitution at nucleotide position 595. The histidine at codon 199 is replaced by tyrosine, an amino acid with similar properties. This mutation was reported in multiple individuals with cystic fibrosis and a second mutation in trans; in vitro studies using HeLa cells expressing this mutation showed a severe processing defect of the CFTR protein (Sosnay PR et al, Nat. Genet. 2013 Oct; 45(10):1160-7). In addition, a disease-causing alteration, p.H199R, has been described in the same codon (D'Apice MR et al, BMC Med. Genet. 2004 Apr; 5:8). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Neuberg Centre For Genomic Medicine, NCGM	RCV000056399	SCV005849438	pathogenic	Cystic fibrosis	2023-06-22	criteria provided, single submitter	clinical testing	The missense c.595C>T (p.His199Tyr) variant in the CFTR gene has been observed in individuals with cystic fibrosis (Castellani, C et al.,2008). Experimental studies have shown that this missense change affects CFTR function (Sosnay, Patrick R et al., 2013). This variant has been reported to the ClinVar database as Pathogenic with a status of reviewed by expert panel. The amino acid Histidine at position 199 is changed to a Tyrosine changing protein sequence and it might alter its composition and physico-chemical properties. This variant has been reported to the ClinVar database as Pathogenic with a status of reviewed by expert panel. Multiple lines of computational evidence (Polyphen - Damaging, SIFT – Damaging and MutationTaster - Disease causing) predict a damaging effect on protein structure and function for this variant. The amino acid Histidine in CFTR is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic.
Natera, Inc.	RCV001831798	SCV002078116	pathogenic	CFTR-related disorder	2017-03-17	no assertion criteria provided	clinical testing