rs747754623
Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1PM2PP5
The NM_000492.4(CFTR):c.3297C>A(p.Phe1099Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000167 in 1,613,322 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. F1099F) has been classified as Likely benign.
Frequency
Consequence
NM_000492.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 5 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CFTR | NM_000492.4 | c.3297C>A | p.Phe1099Leu | missense_variant | 20/27 | ENST00000003084.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CFTR | ENST00000003084.11 | c.3297C>A | p.Phe1099Leu | missense_variant | 20/27 | 1 | NM_000492.4 | P2 | |
ENST00000456270.1 | n.177+4491G>T | intron_variant, non_coding_transcript_variant | 3 |
Frequencies
GnomAD3 genomes AF: 0.0000988 AC: 15AN: 151872Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.0000159 AC: 4AN: 251098Hom.: 0 AF XY: 0.00000737 AC XY: 1AN XY: 135700
GnomAD4 exome AF: 0.00000821 AC: 12AN: 1461450Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3AN XY: 727014
GnomAD4 genome AF: 0.0000988 AC: 15AN: 151872Hom.: 0 Cov.: 31 AF XY: 0.000121 AC XY: 9AN XY: 74152
ClinVar
Submissions by phenotype
Cystic fibrosis Pathogenic:2Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Aug 08, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 21, 2022 | The p.F1099L variant (also known as c.3297C>A), located in coding exon 20 of the CFTR gene, results from a C to A substitution at nucleotide position 3297. The phenylalanine at codon 1099 is replaced by leucine, an amino acid with highly similar properties. The p.F1099L alteration has been reported as a variant of varying clinical consequences (VVCC) (The Clinical and Functional TRanslation of CFTR (CFTR2); available at http://cftr2.org. Accessed December 20, 2022). This variant has been confirmed in trans and identified likely in trans with a CFTR pathogenic variant in multiple individuals with clinical features of cystic fibrosis and CFTR-related disorders (McGinniss MJ et al. Hum Genet, 2005 Dec;118:331-8; Degrugillier F et al. Clin Case Rep, 2019 Nov;7:2128-2134; Zhang X et al. Life (Basel), 2021 Feb;11; Ambry internal data). This variant has 15% of wild type function in The Clinical and Functional TRanslation of CFTR (CFTR2) database (available at http://cftr2.org. Accessed December 20, 2022). Another functional study showed that the maturation of p.F1099L was decreased compared to wild type CFTR (Degrugillier F et al. Clin Case Rep, 2019 Nov;7:2128-2134; Zhang X et al. Life (Basel), 2021 Feb;11). 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 supporting evidence, this alteration is interpreted as a disease-causing mutation. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jul 29, 2022 | This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 1099 of the CFTR protein (p.Phe1099Leu). This variant is present in population databases (rs747754623, gnomAD 0.02%). This missense change has been observed in individual(s) with clinical features of cystic fibrosis and/or cystic fibrosis (PMID: 16189704, 26098992, 33567498). ClinVar contains an entry for this variant (Variation ID: 286681). 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: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). Experimental studies have shown that this missense change affects CFTR function (PMID: 29805046, 33567498). 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. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jun 29, 2023 | Variant summary: CFTR c.3297C>A (p.Phe1099Leu) results in a non-conservative amino acid change located in the ABC transporter type 1, transmembrane domain (IPR011527) of the encoded protein sequence. Three 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 251098 control chromosomes (gnomAD). c.3297C>A has been reported in the literature in the compound heterozygous state together with a pathogenic variant in individuals affected with Cystic Fibrosis, in at least one individual affected with a CFTR-related disorder, and in individuals either with features of CF or who are asymptomatic, presenting with intermmediate sweat chloride levels (e.g. McGinniss_2005, McCague_2019, Degrugillier_2019, Zhang_2021). These data indicate that the variant is likely to be associated with disease, but commonly with a variable and/or milder phenotype. Several publications report experimental evidence evaluating an impact on protein function and found that the variant is associated with reduced protein maturation efficiency and an impaired efflux rate, resulting in approximately 15-25% of WT channel function (e.g. Raraigh_2018, Degrugillier_2019, Zhang_2021). The following publications have been ascertained in the context of this evaluation (PMID: 31788264, 26098992, 30888834, 16189704, 29805046, 26708955, 33567498). Seven submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and reported the variant with conflicting assessments, classifying the variant as either VUS (n=4) or pathogenic (n=2)/likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as likely pathogenic. - |
not provided Pathogenic:2Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Jul 02, 2019 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Clinical Genetics and Genomics, Karolinska University Hospital | May 17, 2019 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Apr 08, 2016 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Oct 18, 2021 | PM2, PM3_strong, PS3 - |
Cystic fibrosis;C0403814:Congenital bilateral aplasia of vas deferens from CFTR mutation Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | - | - - |
CFTR-related disorder Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Jan 16, 2024 | The CFTR c.3297C>A variant is predicted to result in the amino acid substitution p.Phe1099Leu. This variant has been reported in the compound heterozygous state in an asymptomatic 2-month-old diagnosed with cystic fibrosis, in two pediatric patients diagnosed with cystic fibrosis, and in an individual with a negative sweat test who later presented with severe chronic rhinosinusitis (McGinniss et al. 2005. PubMed ID: 16189704; Degrugillier et al. 2019. PubMed ID: 31788264; Zhang et al. 2021 PubMed ID: 33567498). In vitro studies show that this variant results in reduced protein processing and maturation, fewer CFTR channels at the cell surface and, reduced overall CFTR protein function (Raraigh et al. 2018. PubMed ID: 29805046; Degrugillier et al. 2019. PubMed ID: 31788264; Zhang et al. 2021 PubMed ID: 33567498). This variant is listed as a variant of varying clinical consequence (VVCC) in the CFTR2 database. This variant is reported in 0.016% of alleles in individuals of African descent in gnomAD. Taken together, this variant is interpreted as likely pathogenic. - |
Bronchiectasis with or without elevated sweat chloride 1 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 23, 2024 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at