7-117587808-C-T

Variant names:

• chr7-117587808-C-T
• rs76554633
• NM_000492.4:c.1654C>T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000492.4(CFTR):​c.1654C>T​(p.Gln552*) variant causes a stop gained change. The variant was absent in control chromosomes in GnomAD project. 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: not found (cov: 32)
• Consequence: CFTR NM_000492.4 stop_gained
• Clinical Significance: Pathogenic reviewed by expert panel P:10
• Conservation: PhyloP100: 6.96

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]

ACMG classification

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 7-117587808-C-T is Pathogenic according to our data. Variant chr7-117587808-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 7201.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr7-117587808-C-T is described in Lovd as [Pathogenic]. Variant chr7-117587808-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CFTR	NM_000492.4	c.1654C>T	p.Gln552*	stop_gained	Exon 12 of 27	ENST00000003084.11	NP_000483.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CFTR	ENST00000003084.11	c.1654C>T	p.Gln552*	stop_gained	Exon 12 of 27	1	NM_000492.4	ENSP00000003084.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000220 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:10

Revision: reviewed by expert panel

Submissions by phenotype

Cystic fibrosis Pathogenic:7

Jan 01, 1993

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Nov 12, 2019

Myriad Genetics, Inc.

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

NM_000492.3(CFTR):c.1654C>T(Q552*) is classified as pathogenic in the context of cystic fibrosis and is associated with the classic form of disease. Sources cited for classification include the following: PMID 1709778, 7504969 and 23974870. Classification of NM_000492.3(CFTR):c.1654C>T(Q552*) 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.‚Äã -

Mar 17, 2017

CFTR2

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: research

- -

Jul 27, 2022

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Q552* pathogenic mutation (also known as c.1654C>T), located in coding exon 12 of the CFTR gene, results from a C to T substitution at nucleotide position 1654. This changes the amino acid from a glutamine to a stop codon within coding exon 12. In one study, this mutation was found in a patient with cystic fibrosis and pancreatic insufficiency (Devoto et al. Am J Hum Genet 1991;48: 1127). This pathogenic mutation is associated with elevated sweat chloride levels, pancreatic insufficiency, and decreased lung function (Sosnay PR et al. Nat Genet. 2013;45(10):1160-1167). 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. -

Mar 31, 2021

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: CFTR c.1654C>T (p.Gln552X) 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. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 250858 control chromosomes. c.1654C>T has been reported in the literature in multiple individuals affected with Cystic Fibrosis (example, Sosnay_2013). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories and an expert panel (CFTR2) have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Nov 05, 2018

Mendelics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 22, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in CFTR are known to be pathogenic (PMID: 1695717, 7691345, 9725922). This sequence change creates a premature translational stop signal (p.Gln552*) in the CFTR gene. It is expected to result in an absent or disrupted protein product. This variant has been observed in many individuals affected with cystic fibrosis (PMID: 1709778, 18456578, 23974870, 25910067). ClinVar contains an entry for this variant (Variation ID: 7201). This variant is not present in population databases (ExAC no frequency). -

CFTR-related disorder Pathogenic:2

Mar 17, 2017

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 28, 2023

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The CFTR c.1654C>T variant is predicted to result in premature protein termination (p.Gln552*). This variant has been reported in multiple individuals with cystic fibrosis and is associated with elevated sweat chloride levels, pancreatic insufficiency, and decreased lung function (Devoto et al. 1991. PubMed ID: 1709778, Sosnay et al. 2013. PubMed ID: 23974870). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Nonsense variants in CFTR are expected to be pathogenic. This variant is interpreted as pathogenic. -

Bronchiectasis with or without elevated sweat chloride 1 Pathogenic:1

Sep 05, 2023

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	40
DANN	Uncertain	1.0
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Uncertain	0.96	D
Vest4		0.96
GERP RS		5.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.17		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

Other links and lift over

dbSNP: rs76554633; hg19: chr7-117227862;