chr7-117664821-T-C
Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1PM2PM5PP3_ModeratePP5
The NM_000492.4(CFTR):āc.4097T>Cā(p.Ile1366Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000118 in 1,614,030 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I1366N) has been classified as Pathogenic.
Frequency
Consequence
NM_000492.4 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Likely_pathogenic. Variant got 9 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CFTR | NM_000492.4 | c.4097T>C | p.Ile1366Thr | missense_variant | 25/27 | ENST00000003084.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CFTR | ENST00000003084.11 | c.4097T>C | p.Ile1366Thr | missense_variant | 25/27 | 1 | NM_000492.4 | P2 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152176Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000119 AC: 3AN: 251286Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135796
GnomAD4 exome AF: 0.0000123 AC: 18AN: 1461736Hom.: 0 Cov.: 32 AF XY: 0.0000110 AC XY: 8AN XY: 727188
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152294Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74474
ClinVar
Submissions by phenotype
Cystic fibrosis Pathogenic:1Uncertain:4
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Jun 02, 2017 | - - |
Likely pathogenic, criteria provided, single submitter | curation | Institute of Human Genetics, University of Leipzig Medical Center | Jan 19, 2023 | 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: PM2_SUP, PM5_STR, PP3 - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Aug 31, 2021 | This sequence change replaces isoleucine with threonine at codon 1366 of the CFTR protein (p.Ile1366Thr). The isoleucine residue is highly conserved and there is a moderate physicochemical difference between isoleucine and threonine. This variant is present in population databases (rs200955612, ExAC 0.009%). This missense change has been observed in individual(s) with congenital bilateral absence of the vas defense (PMID: 21520337). ClinVar contains an entry for this variant (Variation ID: 526019). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Apr 01, 2022 | The p.I1366T variant (also known as c.4097T>C), located in coding exon 25 of the CFTR gene, results from a T to C substitution at nucleotide position 4097. The isoleucine at codon 1366 is replaced by threonine, an amino acid with similar properties. This alteration has been reported in a subject with congenital bilateral absence of the vas deferens (CBAVD) and in one ostensibly healthy individual (Le Maréchal C et al. Hum. Genet., 2001 Apr;108:290-8; Steiner B et al. Hum. Mutat., 2011 Aug;32:912-20). Another alteration affecting the same amino acid, p.I1366N (c.4097T>A), has been reported in a cystic fibrosis (CF) cohort (Kenková P et al. J. Cyst. Fibros., 2013 Sep;12:532-7). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
not provided Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Aug 13, 2020 | The CFTR c.4097T>C; p.Ile1366Thr variant (rs200955612) is reported in the literature in the heterozygous state in individuals affected with congenital bilateral absence of the vas deferens and also in healthy carriers (Le Marechal 2001, Steiner 2011). This variant is reported in ClinVar (Variation ID: 526019), and is only observed on three alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. The isoleucine at codon 1366 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Additionally, other variants at this codon (c.4097T>A; p.Ile1366Asn; c.4096A>T; p.Ile1366Phe) have been reported in individuals with cystic fibrosis (see link to CFTR2 database, Arslan 2020). However, given the lack of clinical and functional data, the significance of the p.Ile1366Thr variant is uncertain at this time. References: Link to CFTR2 database: https://cftr2.org/ Arslan AB et al. A Novel Pathogenic Variant of the CFTR Gene in a Patient with Cystic Fibrosis Phenotype-c.4096A?>?T. J Pediatr Genet. 2020;9(1):40-43. Le Marechal C et al. Complete and rapid scanning of the cystic fibrosis transmembrane conductance regulator (CFTR) gene by denaturing high-performance liquid chromatography (D-HPLC): major implications for genetic counselling. Hum Genet. 2001;108(4):290-298. Steiner B et al. Common CFTR haplotypes and susceptibility to chronic pancreatitis and congenital bilateral absence of the vas deferens. Hum Mutat. 2012 Feb;33(2):456. Hum Mutat. 2011;32(8):912-920. - |
Uncertain significance, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
CFTR-related disorder Pathogenic:1
Pathogenic, criteria provided, single submitter | curation | CFTR-France | Jan 29, 2018 | - - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Apr 10, 2023 | Variant summary: CFTR c.4097T>C (p.Ile1366Thr) results in a non-conservative amino acid change located in the ABC transporter-like, ATP-binding domain (IPR003439) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 252084 control chromosomes (gnomAD, Steiner_2011, Berg_2013). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.4097T>C has been reported in the literature in individuals affected with Congenital Bilateral Absence Of The Vas Deferens (Steiner_2011) and Cystic Fibrosis (Feuillet_Fieux_2002, Raraigh_2022). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Other missense variants impacting codon 1366 have been described as pathogenic (c.4097T>A [p.Ile1366Asn] ClinVar:551822) or of uncertain significance (c.4096A>T [p.Ile1366Phe] ClinVar:632751). Seven ClinVar submitters have assessed the variant since 2014: five classified the variant as uncertain significance, one as likely pathogenic, and one as pathogenic. Based on the evidence outlined above, the variant was classified as uncertain significance. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at