rs397508736
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PP3_StrongPP5_Very_Strong
The NM_000492.4(CFTR):c.494T>C(p.Leu165Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000429 in 1,398,736 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 Pathogenic (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L165F) has been classified as Uncertain significance.
Frequency
Consequence
NM_000492.4 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CFTR | NM_000492.4 | c.494T>C | p.Leu165Ser | missense_variant | 5/27 | ENST00000003084.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CFTR | ENST00000003084.11 | c.494T>C | p.Leu165Ser | missense_variant | 5/27 | 1 | NM_000492.4 | P2 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome AF: 0.00000429 AC: 6AN: 1398736Hom.: 0 Cov.: 24 AF XY: 0.00000572 AC XY: 4AN XY: 699394
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Cystic fibrosis Pathogenic:4Other:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | May 22, 2024 | The p.L165S pathogenic mutation (also known as c.494T>C), located in coding exon 5 of the CFTR gene, results from a T to C substitution at nucleotide position 494. The leucine at codon 165 is replaced by serine, an amino acid with dissimilar properties. This variant has been identified in the homozygous state and/or in conjunction with other CFTR variant(s) in individual(s) who met clinical criteria for cystic fibrosis; in at least one instance, the variants were identified in trans (Calcedo R et al. Hum Gene Ther Clin Dev, 2013 Sep;24:108-15; Gaitch N et al. Pancreatology Apr;2016:515-22; De Wachter E et al. Orphanet J Rare Dis, 2017 Aug;12:142). This variant has also been reported in multiple individuals with an elevated sweat chloride level and has <10% of wild type function in The Clinical and Functional TRanslation of CFTR (CFTR2) database (available at http://cftr2.org. Accessed 05/20/2024; Raraigh KS et al. Am J Hum Genet, 2018 Jun;102:1062-1077). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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 variant is interpreted as a disease-causing mutation. - |
not provided, no classification provided | literature only | ClinVar Staff, National Center for Biotechnology Information (NCBI) | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Mar 09, 2024 | Variant summary: CFTR c.494T>C (p.Leu165Ser) results in a non-conservative amino acid change located in the ABC transporter type 1, transmembrane domain (IPR011527) of 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 249460 control chromosomes. c.494T>C has been reported in the literature as a compound heterozygous genotype in multiple individuals affected with Cystic Fibrosis enrolled in the Clinical and Functional Translation of CFTR (CFTR2) project (example, McCague_2019). These data indicate that the variant is very likely to be associated with disease. The following publication have been ascertained in the context of this evaluation (PMID: 30888834). ClinVar contains an entry for this variant (Variation ID: 53976). Based on the evidence outlined above, the variant was classified as pathogenic. - |
Pathogenic, reviewed by expert panel | research | CFTR2 | Dec 08, 2017 | - - |
Pathogenic, criteria provided, single submitter | curation | CFTR-France | Jan 29, 2018 | - - |
Multiple acyl-CoA dehydrogenase deficiency Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Mar 09, 2024 | Variant summary: ETFA c.494T>C (p.Val165Ala) results in a non-conservative amino acid change located in the Electron transfer flavoprotein, alpha/beta-subunit, N-terminal domain (IPR014730) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 251386 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.494T>C has been reported in the literature in individuals affected with Glutaric Aciduria, Type 2a. 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as uncertain significance. - |
CFTR-related disorder Pathogenic:1
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Jul 29, 2021 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at