rs397508272
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_000492.4(CFTR):āc.169T>Cā(p.Trp57Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000346 in 1,446,526 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 Likely pathogenic (ā ā ). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. W57G) 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 Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CFTR | NM_000492.4 | c.169T>C | p.Trp57Arg | missense_variant | 3/27 | ENST00000003084.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CFTR | ENST00000003084.11 | c.169T>C | p.Trp57Arg | missense_variant | 3/27 | 1 | NM_000492.4 | P2 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD4 exome AF: 0.00000346 AC: 5AN: 1446526Hom.: 0 Cov.: 28 AF XY: 0.00000416 AC XY: 3AN XY: 720792
GnomAD4 genome ? Cov.: 33
ClinVar
Submissions by phenotype
Cystic fibrosis Pathogenic:4Other:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jun 15, 2023 | Variant summary: CFTR c.169T>C (p.Trp57Arg) 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 250754 control chromosomes. c.169T>C has been reported in the literature in individuals affected with Cystic Fibrosis (Duursma_2022, VanBiervliet_2018, Raraigh_2022, Sickkids_database). In addition another missense variant altering this amino acid (p.Trp57Gly) has been classified as pathogenic in ClinVar, supporting the functional importance of this residue of the protein. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 27, 2021 | 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. This variant disrupts the p.Trp57 amino acid residue in CFTR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7544319, 29805046). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has been observed in individual(s) with clinical features of cystic fibrosis (PMID: 28830496, 16051530, Invitae). ClinVar contains an entry for this variant (Variation ID: 53346). This variant is present in population databases (rs397508272). This sequence change replaces tryptophan with arginine at codon 57 of the CFTR protein (p.Trp57Arg). The tryptophan residue is highly conserved and there is a moderate physicochemical difference between tryptophan and arginine. - |
not provided, no classification provided | literature only | ClinVar Staff, National Center for Biotechnology Information (NCBI) | - | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Jul 22, 2021 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Apr 10, 2023 | The p.W57R variant (also known as c.169T>C), located in coding exon 3 of the CFTR gene, results from a T to C substitution at nucleotide position 169. The tryptophan at codon 57 is replaced by arginine, an amino acid with dissimilar properties. This variant has been detected in conjunction with a pathogenic mutation in CFTR by our laboratory; however, the phase (whether in cis or trans) is not known. This alteration has also been identified in multiple individuals diagnosed with cystic fibrosis (Kinnunen S et al. J. Cyst. Fibros., 2005 Dec;4:233-7; De Wachter E et al. Orphanet J Rare Dis, 2017 Aug;12:142; Auzenbaha M et al. Diagnostics (Basel), 2022 Nov;12:). Based on internal structural analysis, this alteration is more disruptive than known pathogenic variants nearby (Liu F et al. Cell, 2017 Mar;169:85-95.e8). Furthermore, an in vitro study showed that this tryptophan residue is essential for processing of the CFTR protein (Cormet-Boyaka E et al. Proc. Natl. Acad. Sci. U.S.A., 2004 May;101:8221-6). 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. - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Clinical Genetics and Genomics, Karolinska University Hospital | Oct 10, 2019 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at