Submissions for variant NM_000492.4(CFTR):c.1007T>A (p.Ile336Lys)

dbSNP: rs397508139

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
CFTR2	RCV000056337	SCV000071505	pathogenic	Cystic fibrosis	2017-03-17	reviewed by expert panel	research
Eurofins Ntd Llc (ga)	RCV000593715	SCV000700803	pathogenic	not provided	2017-03-15	criteria provided, single submitter	clinical testing
Mendelics	RCV000056337	SCV000886154	pathogenic	Cystic fibrosis	2018-11-05	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000593715	SCV000888064	pathogenic	not provided	2023-08-15	criteria provided, single submitter	clinical testing	The CFTR c.1007T>A (p.Ile336Lys) variant has been reported in the published literature in individuals with cystic fibrosis (PMID: 7508414 (1993), 7505690 (1993), 19318346 (2009), 24586523 (2014)). This variant has also been reported in cystic fibrosis related disorders including congenital bilateral absence of the vas deferens (CBAVD) (PMID: 9272157 (1997)) and pancreatitis (PMID: 10950058 (2000)). Published functional studies showed that this variant affects CFTR protein function (PMID: 23974870 (2013), 23891399 (2014), 29805046 (2018), 30046002 (2018)). The frequency of this variant in the general population, 0.000004 (1/251238 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Based on the available information, this variant is classified as pathogenic.
Baylor Genetics	RCV001004247	SCV001163123	pathogenic	Cystic fibrosis; Congenital bilateral aplasia of vas deferens from CFTR mutation		criteria provided, single submitter	clinical testing
CFTR-France	RCV000056337	SCV001169455	pathogenic	Cystic fibrosis	2018-01-29	criteria provided, single submitter	curation
Labcorp Genetics (formerly Invitae), Labcorp	RCV000056337	SCV001582757	pathogenic	Cystic fibrosis	2023-11-25	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with lysine, which is basic and polar, at codon 336 of the CFTR protein (p.Ile336Lys). This variant is present in population databases (rs397508139, gnomAD 0.0009%). This missense change has been observed in individual(s) with cystic fibrosis (PMID: 7508414, 9272157, 19318346, 24586523). 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: 53162). 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, 29805046, 30046002). For these reasons, this variant has been classified as Pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV000593715	SCV001962089	pathogenic	not provided	2021-07-01	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000593715	SCV002525768	pathogenic	not provided	2021-08-05	criteria provided, single submitter	clinical testing	PP3, PP5, PM2, PM3_very_strong, PS3
Institute of Human Genetics, University of Leipzig Medical Center	RCV000056337	SCV002573961	likely pathogenic	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: PS3_MOD, PM2_SUP, PM3_STR, PP3, PP4
Ambry Genetics	RCV000056337	SCV002730966	pathogenic	Cystic fibrosis	2022-02-07	criteria provided, single submitter	clinical testing	The p.I336K pathogenic mutation (also known as c.1007T>A), located in coding exon 8 of the CFTR gene, results from a T to A substitution at nucleotide position 1007. The isoleucine at codon 336 is replaced by lysine, an amino acid with dissimilar properties. This pathogenic mutation has been reported in multiple cystic fibrosis (CF) patients who have a second pathogenic mutation in trans. This mutation is associated with elevated sweat chloride levels, decreased lung function, and Pseudomonas infection; CF patients with this mutation are more likely to be pancreatic sufficient (Sosnay PR, Nat. Genet. 2013 Oct; 45(10):1160-7, Supplementary Table). In addition, a functional study of this mutation demonstrated that this alteration significantly decreases the amount of normal mature CFTR protein and chloride transport activity compared to the wild-type allele (Van Goor F, J. Cyst. Fibros. 2014; 13(1):29-36). Based on the supporting evidence, p.I336K is interpreted as a disease-causing mutation.
Johns Hopkins Genomics, Johns Hopkins University	RCV000056337	SCV003839070	pathogenic	Cystic fibrosis	2023-02-13	criteria provided, single submitter	clinical testing	Disease-causing CFTR variant. See www.CFTR2.org for phenotype information.
Baylor Genetics	RCV003473440	SCV004213487	pathogenic	Bronchiectasis with or without elevated sweat chloride 1	2023-06-18	criteria provided, single submitter	clinical testing
Counsyl	RCV000056337	SCV000220695	pathogenic	Cystic fibrosis	2019-07-07	no assertion criteria provided	clinical testing
Natera, Inc.	RCV001826607	SCV002078179	pathogenic	CFTR-related disorder	2017-03-17	no assertion criteria provided	clinical testing