Submissions for variant NM_000492.4(CFTR):c.1853T>C (p.Ile618Thr)

gnomAD frequency: 0.00016  dbSNP: rs139468767

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000790746	SCV000226031	pathogenic	not provided	2017-01-16	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000046494	SCV000696878	pathogenic	Cystic fibrosis	2022-03-04	criteria provided, single submitter	clinical testing	Variant summary: Variant summary: CFTR c.1853T>C (p.Ile618Thr) results in a non-conservative amino acid change located in the ABC transporter-like domain (IPR003439) and AAA+ ATPase domain (IPR003593) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function (ACMG PP3). The variant allele was found at a frequency of 3.8e-05 in 262104 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in CFTR causing Non-classic Cystic Fibrosis (3.8e-05 vs 0.013), allowing no conclusion about variant significance. The variant, c.1853T>C, has been reported in the literature in compound heterozygosity with p.F508del or p.G542X in at-least three individuals affected with Non-classic (Pancreatically sufficient/mild phenotypes) Cystic Fibrosis (Macek 1997, Sousa 2012, Faria_2017). These data indicate that the variant may be associated with disease although multiple publications reporting the same patients confound distinct ascertainment (example, Vankeerberghen_1998, Marson_2012A, Marson_2013, Guimbellot_2017, Goncalves_2018, Pereira_2019, Faria_2017). Additionally, this variant has been observed in compound heterozygosity with other classic CFTR mutations such as p.A559T (c.1675G>A), p.F508del (c.1521_1523delCTT) and p.Ser1255X (c.3764C>A) in at-least three patients (a pair of sibs and two other distinct patients) sequenced for the CFTR gene at our laboratory. Detailed clinical information was available on one of these patients who was confirmed to have a known diagnosis of pancreatically insufficient CF with elevated sweat chloride levels, positivity for CF pathogens, severe baseline lung disease, and sinusitis. As the compound heterozygous genotypes observed in our laboratory are distinct (p.A559T and p.Ser1255X) from those reported in the literature, these data indicate that the variant is likely to be associated with disease (ACMG PP4). One publication, Pasyk_1998, reported this variant exhibits <50% of normal activity as chloride channel (ACMG PS3) while another publication, Vankeerberghen_1998, not providing primary data, reported this variant as resulting in abnormal processing leading to no or minimal functional CFTR proteins appearing at the cell membranes. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and a complete consensus (Likely Pathogenic, n=5, Pathogenic, n=2). Some submitters cite overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as pathogenic.
Mendelics	RCV000046494	SCV000886317	pathogenic	Cystic fibrosis	2018-11-05	criteria provided, single submitter	clinical testing
Johns Hopkins Genomics, Johns Hopkins University	RCV000046494	SCV000886895	likely pathogenic	Cystic fibrosis	2019-03-01	criteria provided, single submitter	clinical testing	This CFTR variant (rs139468767) has been previously reported and is rare in large population datasets (gnomAD: 10/261916 total alleles; 0.003818%; no homozygotes). There are conflicting interpretations of the pathogenicity of this variant in ClinVar. Two submitters classified it as pathogenic and a third as a variant of uncertain clinical significance. Independent functional studies determined that this protein does not mature into its fully glycosylated state. Additionally, if any protein is properly trafficked, it is predicted to have reduced chloride conductance. This variant is considered likely pathogenic.
Baylor Genetics	RCV001004276	SCV001163152	likely pathogenic	Cystic fibrosis; Congenital bilateral aplasia of vas deferens from CFTR mutation		criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000046494	SCV001173928	likely pathogenic	Cystic fibrosis	2024-01-17	criteria provided, single submitter	clinical testing	The p.I618T variant (also known as c.1853T>C), located in coding exon 14 of the CFTR gene, results from a T to C substitution at nucleotide position 1853. The isoleucine at codon 618 is replaced by threonine, an amino acid with similar properties. In a cohort of individuals with cystic fibrosis, this variant was identified in one individual in conjunction with p.G542*; however, specific clinical details and the phase of the variants were not provided (Gon&ccedil;alves AC et al. J Pediatr (Rio J), 2018 May;pii: S0021-7557(17)31053-7). Studies have demonstrated that this variant results in decreased chloride channel activity and abnormal protein processing (Pasyk EA et al. J. Biol. Chem., 1998 Nov;273:31759-64; Vankeerberghen A et al. Hum. Mol. Genet., 1998 Oct;7:1761-9). This variant has been reported as a variant of varying clinical consequences (VVCC) (Sosnay PR et al. Pediatr. Clin. North Am., 2016 08;63:585-98; The Clinical and Functional TRanslation of CFTR (CFTR2); available at http://cftr2.org. Accessed September 29, 2020). This amino acid position is well 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.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000790746	SCV001473402	likely pathogenic	not provided	2020-01-10	criteria provided, single submitter	clinical testing	The CFTR c.1853T>C; p.Ile618Thr variant (rs139468767) is reported in the literature in multiple individuals affected with cystic fibrosis who also carry a pathogenic variant presumed to be on the opposite chromosome (Macek 1997, Marson 2012). This variant is reported in ClinVar (Variation ID: 53404), and is only observed on ten alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. The isoleucine at codon 618 is moderately conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Functional assays show reduced cell surface expression and channel function (Pasyk 1998, Vankeerberghen 1998). Based on available information, this variant is considered to be likely pathogenic. References: Macek M et al. Identification of common cystic fibrosis mutations in African-Americans with cystic fibrosis increases the detection rate to 75 percent. Am J Hum Genet. 1997 60(5):1122-7. Marson FA et al. The ACE gene D/I polymorphism as a modulator of severity of cystic fibrosis. BMC Pulm Med. 2012 Aug 8;12:41. Pasyk EA et al. A conserved region of the R domain of cystic fibrosis transmembrane conductance regulator is important in processing and function. J Biol Chem. 1998 Nov 27;273(48):31759-64. Vankeerberghen A et al. Characterization of 19 disease-associated missense mutations in the regulatory domain of the cystic fibrosis transmembrane conductance regulator. Hum Mol Genet. 1998 7(11):1761-9.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000046494	SCV001576371	likely pathogenic	Cystic fibrosis	2023-12-11	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 618 of the CFTR protein (p.Ile618Thr). This variant is present in population databases (rs139468767, gnomAD 0.04%). This missense change has been observed in individual(s) with cystic fibrosis (PMID: 9150159, 23857699; external communication, http//www.genet.sickkids.on.ca/). This variant is also known as c.1985T>C. ClinVar contains an entry for this variant (Variation ID: 53404). 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: 9736778, 9822639). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Mayo Clinic Laboratories, Mayo Clinic	RCV000790746	SCV001714837	likely pathogenic	not provided	2021-07-29	criteria provided, single submitter	clinical testing	PP3, PM2, PM3_strong, PS3
Fulgent Genetics, Fulgent Genetics	RCV002490611	SCV002810431	likely pathogenic	Bronchiectasis with or without elevated sweat chloride 1; Cystic fibrosis; Hereditary pancreatitis; Congenital bilateral aplasia of vas deferens from CFTR mutation	2021-07-22	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003473470	SCV004213339	likely pathogenic	Bronchiectasis with or without elevated sweat chloride 1	2024-03-27	criteria provided, single submitter	clinical testing
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	RCV000046494	SCV004244653	likely pathogenic	Cystic fibrosis	2023-10-26	criteria provided, single submitter	clinical testing	PS3, PM2, PM3, PP3
PreventionGenetics, part of Exact Sciences	RCV004734604	SCV005352671	likely pathogenic	CFTR-related disorder	2024-08-11	no assertion criteria provided	clinical testing	The CFTR c.1853T>C variant is predicted to result in the amino acid substitution p.Ile618Thr. This variant has been reported as pathogenic in patients with cystic fibrosis (Macek et al. 1997. PubMed ID: 9150159; Faria et al. 2017. PubMed ID: 29124052; Sousa et al. 2012. PubMed ID: 23082198; Pereira et al. 2019. PubMed ID: 30996306), and is listed in ClinVar as pathogenic and likely pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/53404/). This variant is reported in 0.041% of alleles in individuals of African descent in gnomAD. This variant is interpreted as likely pathogenic.