Submissions for variant NM_000492.4(CFTR):c.3068T>G (p.Ile1023Arg)

dbSNP: rs756219310

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001226278	SCV000696945	pathogenic	Cystic fibrosis	2024-06-27	criteria provided, single submitter	clinical testing	Variant summary: CFTR c.3068T>G (p.Ile1023Arg) results in a non-conservative amino acid change located in the ABC transporter type 1, transmembrane domain (IPR011527) of the encoded protein sequence. Four of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251076 control chromosomes. c.3068T>G has been reported in the literature in the presumed compound heterozygous, compound heterozygous, or homozygous states multiple individuals affected with Cystic Fibrosis (example, Leung_2017). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect resulted in approximately 1.73% of normal chloride channel conductance relative to wild type (e.g., Bihler_2024). The following publications have been ascertained in the context of this evaluation (PMID: 23089694, 28116329, 22992393, 38388235). ClinVar contains an entry for this variant (Variation ID: 495923). Based on the evidence outlined above, the variant was classified as pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001226278	SCV001398586	pathogenic	Cystic fibrosis	2022-06-15	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This missense change has been observed in individual(s) with cystic fibrosis (PMID: 22992393, 23089694, 28116329). 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: 495923). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). Experimental studies have shown that this missense change affects CFTR function (PMID: 28116329). This sequence change replaces isoleucine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 1023 of the CFTR protein (p.Ile1023Arg). This variant is present in population databases (rs756219310, gnomAD 0.006%).
NxGen MDx	RCV001226278	SCV001573125	likely pathogenic	Cystic fibrosis	2020-05-19	criteria provided, single submitter	clinical testing	This missense variant (c.3068T>G) in a hotspot on exon 19 of CFTR (PM1) and gnomAD databases indicate low allele frequency (PM2). Computational models produce mostly pathogenic verdicts for this variant (PP3). This variant has been reported in heterozygosity with c.1898+5G>T in two Taiwanese brothers with recurrent pneumonia and bronchiolitis. One of the brothers had sweat chloride levels >100 meq/l indicating a diagnosis of cystic fibrosis (Chen el al. PMID 23089694; Liu et al. PMID 22992393). There are 4 additional cases in Leung et al. PMID 28116329 where the authors suggest this variant may be a founder mutation in southern Han Chinese. Leung et al. also conducted functional analysis demonstrating that p.Ile1023Arg leads to a trafficking defect during CFTR maturation without affecting the gating function. We interpret c.3068T>G to be likely pathogenic.
Ambry Genetics	RCV001226278	SCV002753007	likely pathogenic	Cystic fibrosis	2019-08-07	criteria provided, single submitter	clinical testing	The p.I1023R variant (also known as c.3068T>G), located in coding exon 19 of the CFTR gene, results from a T to G substitution at nucleotide position 3068. The isoleucine at codon 1023 is replaced by arginine, an amino acid with similar properties. This variant has been identified in several individuals with symptoms of cystic fibrosis with a second CFTR variant and has been suggested to be a Southern Chinese founder mutation (Chen CH et al. J. Formos. Med. Assoc., 2012 Oct;111:580-3; Liu LC et al. J Microbiol Immunol Infect, 2014 Aug;47:358-61; Leung GK et al. Mol Genet Genomic Med, 2017 Jan;5:40-49). One homozygous individual presented at 4 months of age with elevated sweat chloride levels, respiratory symptoms, and pancreatic insufficiency (Leung GK et al. Mol Genet Genomic Med, 2017 Jan;5:40-49). In HeLa cells, this variant demonstrated reduced levels of mature CFTR protein compared to wild type (Leung GK et al. Mol Genet Genomic Med, 2017 Jan;5:40-49). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Baylor Genetics	RCV003471940	SCV004213332	likely pathogenic	Bronchiectasis with or without elevated sweat chloride 1	2023-12-10	criteria provided, single submitter	clinical testing