7-117667091-C-T

Variant names:

• chr7-117667091-C-T
• rs374705585
• NM_000492.4:c.4426C>T

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1_Moderate PP5_Very_Strong

The NM_000492.4(CFTR):​c.4426C>T​(p.Gln1476*) variant causes a stop gained change. The variant allele was found at a frequency of 0.0000204 in 1,613,752 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 (★★).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000021 (0 hom.)
• Consequence: CFTR NM_000492.4 stop_gained
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:17 U:1
• Conservation: PhyloP100: 7.17
• Publications: 17 publications found

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 Gene-Disease associations (from GenCC):

• cystic fibrosis

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), Myriad Women’s Health, Orphanet
• congenital bilateral absence of vas deferens

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• hereditary chronic pancreatitis

  Inheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.00383 CDS is truncated, and there are 2 pathogenic variants in the truncated region.
• PP5: Variant 7-117667091-C-T is Pathogenic according to our data. Variant chr7-117667091-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 53947.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CFTR	NM_000492.4	c.4426C>T	p.Gln1476*	stop_gained	Exon 27 of 27	ENST00000003084.11	NP_000483.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CFTR	ENST00000003084.11	c.4426C>T	p.Gln1476*	stop_gained	Exon 27 of 27	1	NM_000492.4	ENSP00000003084.6

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152158 Hom.: 0 Cov.: 33

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

GnomAD2 exomes AF: 0.0000199 AC: 5 AN: 250874 AF XY: 0.0000221

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000353

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000205 AC: 30 AN: 1461594 Hom.: 0 Cov.: 32 AF XY: 0.0000206 AC XY: 15 AN XY: 727114

African (AFR) AF: 0.0000299 AC: 1 AN: 33464

American (AMR) AF: 0.00 AC: 0 AN: 44690

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39660

South Asian (SAS) AF: 0.00 AC: 0 AN: 86244

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53406

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.0000261 AC: 29 AN: 1111852

Other (OTH) AF: 0.00 AC: 0 AN: 60384

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152158 Hom.: 0 Cov.: 33 AF XY: 0.0000404 AC XY: 3 AN XY: 74320

African (AFR) AF: 0.00 AC: 0 AN: 41424

American (AMR) AF: 0.00 AC: 0 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68044

Other (OTH) AF: 0.00 AC: 0 AN: 2084

Alfa AF: 0.000268 Hom.: 0

Bravo AF: 0.0000302

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000247 AC: 3

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:17 Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cystic fibrosis Pathogenic:6 Uncertain:1

Aug 28, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Gln1476*) in the CFTR gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 5 amino acid(s) of the CFTR protein. This variant is present in population databases (rs374705585, gnomAD 0.005%). This premature translational stop signal has been observed in individuals with cystic fibrosis (PMID: 11938439, 22020151, 25910067, 28544683). ClinVar contains an entry for this variant (Variation ID: 53947). Algorithms developed to predict the effect of variants on gene product structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this premature translational stop signal affects CFTR function (PMID: 30444886). For these reasons, this variant has been classified as Pathogenic. -

Aug 09, 2024

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Q1476* variant (also known as c.4426C>T), located in coding exon 27 of the CFTR gene, results from a C to T substitution at nucleotide position 4426. This changes the amino acid from a glutamine to a stop codon within coding exon 27. Premature stop codons are typically deleterious in nature, however, this stop codon occurs at the 3' terminus of CFTR, is not expected to trigger nonsense-mediated mRNA decay, and impacts only the last 5 amino acids of the protein. The exact functional impact of these removed amino acids is unknown at this time. However, this variant has been reported in the literature in several individuals who are compound heterozygous for p.Q1476* and p.F508del: one individual with idiopathic pancreatitis was subsequently found to have elevated sweat chloride levels (Audrézet MP et al. Eur. J. Hum. Genet., 2002 Feb;10:100-6), two males had elevated sweat chloride levels, congenital bilateral absence of the vas deferens (CBAVD), pancreatic sufficiency, and normal respiratory function (Bienvenu T et al. Clin. Genet., 2003 Sep;64:266-8), a third male was reported to have CBAVD only (Amato F et al. J Mol Diagn, 2012 Jan;14:81-9), another individual had moderate pulmonary symptoms with nasal polyposis and digital clubbing (Soltysova A et al. Clin Respir J, 2018 Mar;12:1197-1206), and the last individual had a history of bronchiectasis and pseudomonas infection (Sugunaraj JP et al. NPJ Genom Med, 2019 Sep;4:21). This variant has been reported as a variant of varying clinical consequences (VVCC) (Sosnay PR et al. Pediatr. Clin. North Am., 2016 08;63:585-98; The Clinical and Functional TRanslation of CFTR (CFTR2); available at http://cftr2.org. Accessed April 4, 2019). Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Dec 19, 2018

Counsyl

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

-

Baylor Genetics

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Sep 05, 2022

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

This variant was identified in 1 patient with a clinically confirmed diagnosis of cystic fibrosis. The variant was classified in the context of a project re-classifying variants in the German Cystic Fibrosis Registry (Muko.e.V.). Link: https://www.muko.info/angebote/qualitaetsmanagement/register/cf-einrichtungen/mukoweb. Criteria applied: PVS1_MOD, PS3_SUP, PM2_SUP, PM3_STR, PP4 -

May 08, 2017

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: The CFTR c.4426C>T (p.Gln1476X) variant results in a termination codon in the penultimate exon deleting the last four amino acids (Asp-Thr-Arg-Leu). No pathogenic/likely pathogenic truncating variants downstream of this position have been reported in literature, ClinVar and our laboratory and it is outside of some of the commonly known domains (transmembrane domain, ATPase domain and regulator domain) (InterPro). There are no functional studies for this variant as well. Mutation taster predicts a damaging outcome for this variant. This variant was found in 3/120070 control chromosomes including ExAC at a frequency of 0.000025, which does not exceed the estimated maximal expected allele frequency of a pathogenic CFTR variant (0.0129603). In literature, this variant was found in at least 5 CF patients, 5 CBAVD patients, 3 ICP patients and 3 patients reported to be diagnosed of CFTR-RD. Most patients were known to be compound heterozygotes with another pathogenic variant, primarily with p.Phe508del. In addition, two reported CBAVD patients were found to have elevated sweat chloride implying the diagnosis of CF/NC. Although a nonsense variant, severity of disease associated with this variant is widely reported as mild in literature which can be implicated to its location and resuting functional consequence. One clinical laboratory in ClinVar has classified it as pathogenic. Because CF/NC phenotype has been reported with this variant, and because CBAVD and ICP can also be categorized as manifestation of CF, this variant has been classified as pathogenic with respect to CF/NC phenotype. -

May 27, 2020

Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant affects the last exon of CFTR and is predicted to escape nonsense mediated decay (NMD). The c.4426C>T alteration has been previously reported as a compound heterozygous change in multiple patients with variable clinical presentation ranging from cystic fibrosis to congenital absence of vas deference, and other CFTR-related disorders such as chronic pancreatitis (PMID: 21520337, 22020151, 23276700, https://cftr2.org/mutation/general/all_cf/Q1476X). In-vitro studies showed that this variant leads to the expression of a mature truncated form of CFTR that moderately affects the channel functioning and is responsive to treatment with lumacaftor, or a combination of both lumacaftor and tezacaftor (PMID: 30444886). It is present in the heterozygous state in the gnomAD population database at a frequency of 0.002% (6/282280) and thus is presumed to be rare. In silico analyses support a deleterious effect of the c.4426C>T (p.Gln1476Ter) variant on protein function. Based on the available evidence, the c.4426C>T (p.Gln1476Ter) variant is classified as Likely Pathogenic. -

not provided Pathogenic:4

Oct 21, 2022

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This nonsense variant causes the premature termination of CFTR protein synthesis. The frequency of this variant in the general population, 0.000039 (5/128820 chromosomes, http://gnomad.broadinstitute.org), is consistent with pathogenicity. In the published literature, the variant has been reported in individuals with cystic fibrosis (CF) (PMIDs: 28544683 (2017), 23276700 (2013), 12919146 (2003), 11938439 (2002)) and cystic fibrosis related disease (CFRD) (PMIDs: 25910067 (2015), 22020151 (2012), 21679131 (2011), 21520337 (2011), 17449517 (2007), 17003641 (2006), 12919146 (2003)). This variant is often detected in trans with another pathogenic CFTR variant in affected individuals (PMIDs: 28544683 (2017), 25910067 (2015), 22020151 (2012)). Functional studies have demonstrated this variant may mildly impact protein function, but additional studies are needed to determine the global impact of this variant on the CFTR gene or gene products (PMID: 30444886 (2018)). Based on the available information, this variant is classified as pathogenic. -

Aug 30, 2013

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

CFTR: PM3:Very Strong, PM2, PVS1:Moderate -

May 12, 2022

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nonsense variant predicted to result in protein truncation as the last 5 amino acids are lost within the PDZ interaction domain (Moyer et al., 1999), although loss-of-function variants have not been reported downstream of this position in the protein; Published functional studies demonstrate normal protein expression and modulator response, but reduced chloride channel function (Sharma et al., 2018); Classified as a variant of varying clinical consequence in a well-curated database (CFTR2); This variant is associated with the following publications: (PMID: 31589614, 34426522, 30444886, 11938439, 12919146, 10562297, 17449517, 28603918, 21520337, 23276700, 25910067, 22020151, 25087612, 28544683, 21679131, 16784904, 17003641, 12578973, 11504857, 15758663) -

Hereditary pancreatitis Pathogenic:2

May 10, 2021

Sema4, Sema4

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

- -

May 04, 2022

Mendelics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Pathogenic:1

Nov 08, 2016

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cystic fibrosis;C0403814:Congenital bilateral aplasia of vas deferens from CFTR mutation Pathogenic:1

-

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

CFTR-related disorder Pathogenic:1

Jan 29, 2018

CFTR-France

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

- -

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

Mar 28, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Bronchiectasis with or without elevated sweat chloride 1 Pathogenic:1

Feb 06, 2022

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	0.50	D
BayesDel_noAF	Pathogenic	0.66
CADD	Pathogenic	40
DANN	Uncertain	1.0
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.97
FATHMM_MKL	Pathogenic	0.98	D
PhyloP100		7.2
Vest4		0.69
GERP RS		5.5
Mutation Taster		=5/195	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs374705585; hg19: chr7-117307145;