7-117509047-G-T
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000492.4(CFTR):c.178G>T(p.Glu60*) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000441 in 1,608,822 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★★). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_000492.4 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
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CFTR | NM_000492.4 | c.178G>T | p.Glu60* | stop_gained | Exon 3 of 27 | ENST00000003084.11 | NP_000483.3 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000197 AC: 3AN: 152204Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000239 AC: 6AN: 250868Hom.: 0 AF XY: 0.0000369 AC XY: 5AN XY: 135588
GnomAD4 exome AF: 0.0000467 AC: 68AN: 1456618Hom.: 1 Cov.: 29 AF XY: 0.0000400 AC XY: 29AN XY: 725060
GnomAD4 genome AF: 0.0000197 AC: 3AN: 152204Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2AN XY: 74350
ClinVar
Submissions by phenotype
Cystic fibrosis Pathogenic:8
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Variant summary: CFTR c.178G>T (p.Glu60X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 2.4e-05 in 250868 control chromosomes. This variant has been reported in numerous number of CF pts worldwide and is considered as a common disease variant. RT-PCR analysis showed this variant leads to exon skipping resulting <15% mut/wt transcription product (Will_1995). These data indicate that the variant is very likely to be associated with disease. ClinVar contains an entry for this variant (Variation ID: 38730). Based on the evidence outlined above, the variant was classified as pathogenic. -
This sequence change creates a premature translational stop signal (p.Glu60*) in the CFTR gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CFTR are known to be pathogenic (PMID: 1695717, 7691345, 9725922). This variant is present in population databases (rs77284892, gnomAD 0.005%). This premature translational stop signal has been observed in individuals with cystic fibrosis (PMID: 1537190, 7541274, 8477260, 11788090, 15698945). ClinVar contains an entry for this variant (Variation ID: 38730). For these reasons, this variant has been classified as Pathogenic. -
NM_000492.3(CFTR):c.178G>T(E60*) is classified as pathogenic in the context of cystic fibrosis and is associated with the classic form of this disease. Sources cited for classification include the following: PMID 7541274, 9806422, 22658665, 1284534, 18456578 and 23974870. Classification of NM_000492.3(CFTR):c.178G>T(E60*) is based on the following criteria: The variant causes a premature termination codon that is expected to be targeted by nonsense-mediated mRNA decay and is reported in individuals with the relevant phenotype. Please note: this variant was assessed in the context of healthy population screening. -
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Disease-causing CFTR variant. See www.CFTR2.org for phenotype information. -
The p.E60* pathogenic mutation (also known as c.178G>T), located in coding exon 3 of the CFTR gene, results from a G to T substitution at nucleotide position 178. This changes the amino acid from a glutamic acid to a stop codon within coding exon 3. This pathogenic mutation is associated with elevated sweat chloride levels, decreased lung function, and pancreatic insufficiency (Sosnay PR et al. Nat. Genet., 2013 Oct;45:1160-7). In addition, one study showed that when expressed in minigene assay, this mutation resulted in exon 3 skipping approximately one third of the time (Aissat A et al. Hum. Mutat., 2013 Jun;34:873-81). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -
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not provided Pathogenic:5
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The CFTR c.178G>T; p.Glu60Ter variant (rs77284892), is reported in the literature in numerous individuals affected with cystic fibrosis (Dugueperoux 2004, Ooi 2012, Tsui 1992, Sosnay 2013, Will 1995). Cystic fibrosis patients carrying this variant have elevated sweat chloride levels and decreased lung function, and more than 95% exhibit pancreatic insufficiency (Dugueperoux 2004, Ooi 2012, Sosnay 2013). This variant is reported in ClinVar (Variation ID: 38730). This variant is found in the non-Finnish European population with an overall allele frequency of 0.0054% (6/111300 alleles) in the Genome Aggregation Database. This variant induces an early termination codon and is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Consistent with this, analysis of mRNAs from patients carrying the c.178G>T; p.Glu60Ter variant suggest that transcripts with this variant are present at levels <15% of wildtype (Will 1995). This variant can also cause skipping of exon 3 or both exons 3 and 4, events that cause frameshifts in the CFTR transcript (Aissat 2013, Valentine 1998, Will 1995). Based on available information, this variant is considered to be pathogenic. References: Aissat A et al. Combined computational-experimental analyses of CFTR exon strength uncover predictability of exon-skipping level. Hum Mutat. 2013 Jun;34(6):873-81 Dugueperoux I et al. Genotype-phenotype relationship for five CFTR mutations frequently identified in western France. J Cyst Fibros. 2004 Dec;3(4):259-63. Ooi C and Durie PR. Cystic fibrosis transmembrane conductance regulator (CFTR) gene mutations in pancreatitis. J Cyst Fibros. 2012 Sep;11(5):355-62. Tsui L. Mutations and sequence variations detected in the cystic fibrosis transmembrane conductance regulator (CFTR) gene: a report from the Cystic Fibrosis Genetic Analysis Consortium. Hum Mutat. 1992;1(3):197-203. Sosnay et al. Defining the disease liability of variants in the cystic fibrosis transmembrane conductance regulator gene. Nat Genet. 2013 Oct;45(10):1160-7. Valentine CR. The association of nonsense codons with exon skipping. Mutat Res. 1998 Sep;411(2):87-117. Will K et al. Transcript analysis of CFTR nonsense mutations in lymphocytes and nasal epithelial cells from cystic fibrosis patients. Hum Mutat. 1995;5(3):210-20. -
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The nonsense variant causes the premature termination of CFTR protein synthesis. It has been reported in individuals affected with cystic fibrosis and CFTR-related diseases in the published literature (PMIDs: 15698945 (2004), 15776432 (2005), and 18456578 (2008)). Variant was found to occur in 3 or more cases with a lone recessive pathogenic/likely pathogenic variant in the same gene and is damaging to protein function(s) relevant to disease mechanism (PMID 7541274). Therefore, the variant is classified as pathogenic. -
CFTR-related disorder Pathogenic:2
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Cystic fibrosis;C0403814:Congenital bilateral aplasia of vas deferens from CFTR mutation Pathogenic:1
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Cystic fibrosis;C0238339:Hereditary pancreatitis;C0403814:Congenital bilateral aplasia of vas deferens from CFTR mutation;C2749757:Bronchiectasis with or without elevated sweat chloride 1 Pathogenic:1
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Bronchiectasis with or without elevated sweat chloride 1 Pathogenic:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at