7-117509047-G-T

Position:

chr7-117509047-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

Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000047 ( 1 hom. )

Consequence

CFTR
NM_000492.4 stop_gained

Scores

Clinical Significance

Pathogenic reviewed by expert panel P:18

Conservation

PhyloP100: 7.71

Variant links:

Genes affected

CFTR (HGNC:1884): (CF transmembrane conductance regulator) This gene encodes a member of the ATP-binding cassette (ABC) transporter superfamily. The encoded protein functions as a chloride channel, making it unique among members of this protein family, and controls ion and water secretion and absorption in epithelial tissues. Channel activation is mediated by cycles of regulatory domain phosphorylation, ATP-binding by the nucleotide-binding domains, and ATP hydrolysis. Mutations in this gene cause cystic fibrosis, the most common lethal genetic disorder in populations of Northern European descent. The most frequently occurring mutation in cystic fibrosis, DeltaF508, results in impaired folding and trafficking of the encoded protein. Multiple pseudogenes have been identified in the human genome. [provided by RefSeq, Aug 2017]

CFTR links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 7-117509047-G-T is Pathogenic according to our data. Variant chr7-117509047-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 38730.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr7-117509047-G-T is described in Lovd as [Pathogenic]. Variant chr7-117509047-G-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CFTR	NM_000492.4 link	c.178G>T	p.Glu60*	stop_gained	3/27	ENST00000003084.11	NP_000483.3	P13569-1A0A024R730

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CFTR	ENST00000003084.11 link	c.178G>T	p.Glu60*	stop_gained	3/27	1	NM_000492.4	ENSP00000003084.6		P13569-1

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152204

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000239

AC:

AN:

250868

Hom.:

AF XY:

0.0000369

AC XY:

AN XY:

135588

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000529

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000467

AC:

AN:

1456618

Hom.:

Cov.:

AF XY:

0.0000400

AC XY:

AN XY:

725060

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000569

Gnomad4 OTH exome

AF:

0.0000830

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152204

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74350

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000671

Hom.:

Bravo

AF:

0.0000113

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000330

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:18

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Cystic fibrosis

Pathogenic:8

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 23, 2017	Variant summary: The CFTR c.178G>T (p.Glu60X) variant involves the alteration of a conserved nucleotide. One in silico tool predicts a damaging outcome for this variant. This variant was found in 4/121190 control chromosomes at a frequency of 0.000033, which does not exceed the estimated maximal expected allele frequency of a pathogenic CFTR variant (0.0129603). 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). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	curation	CFTR-France	Jan 29, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Johns Hopkins Genomics, Johns Hopkins University	Aug 20, 2022	Disease-causing CFTR variant. See www.CFTR2.org for phenotype information. -
Pathogenic, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, The Hospital for Sick Children	Aug 01, 2019	- -
Pathogenic, reviewed by expert panel	research	CFTR2	Mar 17, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Dec 09, 2019	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	May 31, 2022	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 26, 2023	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. -

not provided

Pathogenic:5

Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Nov 12, 2020	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. -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Aug 22, 2022	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. -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

CFTR-related disorder

Pathogenic:2

Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, The Hospital for Sick Children	Aug 01, 2019	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Mar 17, 2017	- -

Cystic fibrosis;C0403814:Congenital bilateral aplasia of vas deferens from CFTR mutation

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

- -

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

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Nov 05, 2021

- -

Bronchiectasis with or without elevated sweat chloride 1

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Mar 27, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.52

BayesDel_noAF

Pathogenic

0.65

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Pathogenic

1.2

Eigen_PC

Pathogenic

1.1

FATHMM_MKL

Pathogenic

0.98

Vest4

0.90

GERP RS

5.7

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.11

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over