ClinVar Miner

Submissions for variant NM_000492.4(CFTR):c.1853T>C (p.Ile618Thr) (rs139468767)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics 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 likely pathogenic Cystic fibrosis 2020-11-20 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 two individuals affected with Non-classic (Pancreatically sufficient/mild phenotypes) Cystic Fibrosis (Macek 1997, Sousa 2012). 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). 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. Three submitters have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (Likely pathogenic (n=1), Pathogenic (n=2)). Based on the evidence outlined above, the variant was classified as likely pathogenic until additional clinical and functional evidence become available.
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 RCV001013349 SCV001173928 likely pathogenic Inborn genetic diseases 2020-09-29 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). Based on data from gnomAD, the C allele has an overall frequency of <0.01% (10/26916). 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.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001286785 SCV001473402 likely pathogenic none 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.
Invitae RCV000046494 SCV001576371 likely pathogenic Cystic fibrosis 2020-08-11 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with threonine at codon 618 of the CFTR protein (p.Ile618Thr). The isoleucine residue is moderately conserved and there is a moderate physicochemical difference between isoleucine and threonine. This variant is present in population databases (rs139468767, ExAC 0.01%). This variant has been observed in individual(s) with cystic fibrosis (PMID: 9150159, 23857699, http://www.genet.sickkids.on.ca/, external communication). This variant is also known as c.1985T>C. ClinVar contains an entry for this variant (Variation ID: 53404). This variant has been reportedto affect CFTR protein function (PMID: 9822639, 9736778). 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 2019-11-11 criteria provided, single submitter clinical testing PS3, PM3

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