rs397508634
Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1PM2PP3_StrongPP5
The NM_000492.4(CFTR):c.3896C>T(p.Thr1299Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000282 in 1,419,508 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. T1299A) has been classified as Uncertain significance.
Frequency
Consequence
NM_000492.4 missense
Scores
Clinical Significance
Conservation
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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.3896C>T | p.Thr1299Ile | missense_variant | 24/27 | ENST00000003084.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CFTR | ENST00000003084.11 | c.3896C>T | p.Thr1299Ile | missense_variant | 24/27 | 1 | NM_000492.4 | P2 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome AF: 0.00000282 AC: 4AN: 1419508Hom.: 0 Cov.: 26 AF XY: 0.00000282 AC XY: 2AN XY: 708348
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Cystic fibrosis Pathogenic:2Uncertain:2Other:1
Uncertain significance, criteria provided, single submitter | clinical testing | Mendelics | Nov 05, 2018 | - - |
not provided, no classification provided | literature only | ClinVar Staff, National Center for Biotechnology Information (NCBI) | - | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Sep 05, 2021 | - - |
Likely pathogenic, criteria provided, single submitter | curation | Institute of Human Genetics, University of Leipzig Medical Center | Sep 05, 2022 | This variant was identified in 4 unrelated patients 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, PM3_STR, PP3 - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Dec 20, 2023 | Variant summary: CFTR c.3896C>T (p.Thr1299Ile) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 249246 control chromosomes (gnomAD). c.3896C>T has been reported in the literature in multiple individuals affected with cystic fibrosis (e.g. Liechti-Gallati_1999, Rock_2005, Alonso_2007, Ooi_2015, Minso_2020, Gonska_2021), including patients who carried a 2nd pathogenic variant. These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 10439967, 16202788, 17331079, 25963003, 33020115, 34814176). Six submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, and classified the variant as likely pathogenic (n=1) or VUS (n=5). Based on the evidence outlined above, the variant was classified as likely pathogenic. - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Dec 13, 2018 | The CFTR c.3896C>T; p.Thr1299Ile variant (rs397508634), is reported in the literature in individuals with a suspected diagnosis of cystic fibrosis, including with the common pathogenic F508del variant on the opposite chromosome (Alonso 2007, Liechti-Gallati 1999, Ooi 2015, Rock 2005). This variant is reported in ClinVar (Variation ID: 53844), and is absent from general population databases (1000 Genomes Project, Exome Variant Server, and Genome Aggregation Database), indicating it is not a common polymorphism. The threonine at codon 1299 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. However, given the lack of clinical and functional data, the significance of the p.Thr1299Ile variant is uncertain at this time. References: Alonso MJ et al. Spectrum of mutations in the CFTR gene in cystic fibrosis patients of Spanish ancestry. Ann Hum Genet. 2007 Mar;71(Pt 2):194-201. Liechti-Gallati S et al. Two buffer PAGE system-based SSCP/HD analysis: a general protocol for rapid and sensitive mutation screening in cystic fibrosis and any other human genetic disease. Eur J Hum Genet. 1999 Jul;7(5):590-8. Ooi CY et al. Inconclusive diagnosis of cystic fibrosis after newborn screening. Pediatrics. 2015 Jun;135(6):e1377-85. Rock MJ et al. Newborn screening for cystic fibrosis in Wisconsin: nine-year experience with routine trypsinogen/DNA testing. J Pediatr. 2005 Sep;147(3 Suppl):S73-7. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Jan 14, 2021 | - - |
CFTR-related disorder Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Dec 17, 2020 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at