7-117587778-G-T

Position:

• chr7-117587778-G-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.1624G>T​(p.Gly542Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.000363 in 1,612,120 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 (★★★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.00030 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00037 (0 hom.)
• Consequence: CFTR NM_000492.4 stop_gained
• Clinical Significance: Pathogenic practice guideline P:35 O:3
• Conservation: PhyloP100: 4.51

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 7-117587778-G-T is Pathogenic according to our data. Variant chr7-117587778-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 7115.Status of the report is practice_guideline, 4 stars. Variant chr7-117587778-G-T is described in Lovd as [Pathogenic]. Variant chr7-117587778-G-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CFTR	NM_000492.4	c.1624G>T	p.Gly542Ter	stop_gained	12/27	ENST00000003084.11	NP_000483.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CFTR	ENST00000003084.11	c.1624G>T	p.Gly542Ter	stop_gained	12/27	1	NM_000492.4	ENSP00000003084	P2

Frequencies

GnomAD3 genomes AF: 0.000296 AC: 45 AN: 152178 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000524

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000456

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000339 AC: 85 AN: 250908 Hom.: 0 AF XY: 0.000347 AC XY: 47 AN XY: 135578

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.000784

Gnomad ASJ exome AF: 0.00149

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000353

Gnomad OTH exome AF: 0.000327

GnomAD4 exome AF: 0.000370 AC: 540 AN: 1459824 Hom.: 0 Cov.: 28 AF XY: 0.000346 AC XY: 251 AN XY: 726294

Gnomad4 AFR exome AF: 0.0000599

Gnomad4 AMR exome AF: 0.000695

Gnomad4 ASJ exome AF: 0.00138

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000401

Gnomad4 OTH exome AF: 0.000398

GnomAD4 genome AF: 0.000295 AC: 45 AN: 152296 Hom.: 0 Cov.: 32 AF XY: 0.000309 AC XY: 23 AN XY: 74466

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.000523

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000456

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000409 Hom.: 0

Bravo AF: 0.000393

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00186 AC: 16

ExAC AF: 0.000264 AC: 32

EpiCase AF: 0.000382

EpiControl AF: 0.000830

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:35 Other:3

Revision: practice guideline

Submissions by phenotype

Cystic fibrosis Pathogenic:17 Other:1

Pathogenic, practice guideline	curation	American College of Medical Genetics and Genomics (ACMG)	Mar 03, 2004	- -
Pathogenic, criteria provided, single submitter	clinical testing	New York Genome Center	May 31, 2023	The inherited c.1624G>T (p.Gly542Ter) stop-gained variant identified in exon 12 (of 27) of the CFTR gene has been reported in multiple affected individuals in the literature and is recognized as a disease-causing variant (PMID: 15371902, 23974870, CFTR2 database: https://cftr2.org). The variant creates a premature translation termination codon and is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. Predicted loss-of-function variants in CFTR are known to be pathogenic (PMID: 1695717, PMID: 12940920). This variant has been reported in the ClinVar database as Pathogenic by multiple independent laboratories [Variation ID:7115]. Based on the available evidence, the inherited c.1624G>T (p.Gly542Ter) stop-gained variant identified in the CFTR gene is reported as Pathogenic. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 01, 1997	- -
Pathogenic, reviewed by expert panel	research	CFTR2	Mar 17, 2017	- -
not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	This sequence change creates a premature translational stop signal (p.Gly542*) 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 (rs113993959, gnomAD 0.1%). This premature translational stop signal has been observed in individual(s) with cystic fibrosis (PMID: 15371902, 23974870). This variant is also known as G542X. ClinVar contains an entry for this variant (Variation ID: 7115). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Oct 25, 2017	The CFTR c.1624G>T (p.Gly542Ter) variant is a stop-gained variant predicted to result in premature termination of the protein. The p.Gly542Ter variant, a well-described pathogenic variant, is reported at a frequency of 2.64% among a pan-ethnic population clinically diagnosed with CFTR-related disorders, and recognised as the second most common pathogenic variant after p.Phe508del (Watson et al. 2004). The p.Gly542Ter variant is one of the 23 pathogenic variants recommended by the ACMG for general population cystic fibrosis carrier screening. Across a selection of the available literature, the p.Gly542Ter variant was identified in at least 40 individuals with cystic fibrosis, including five unrelated individuals in a homozygous state, 11 unrelated individuals in a compound heterozygous state, and 24 individuals in a heterozygous state (de Gracia et al. 2005; Chavez-Saldana et al. 2010). Five of the compound heterozygotes carried p.Phe508del on the second allele (de Gracia et al. 2005). Control data were unavailable for this variant in these studies but it is reported at a frequency of 0.001860 in the European American population of the Exome Sequencing Project. Based on the evidence and the potential impact of stop-gained variants, the p.Gly542Ter variant is classified as pathogenic for CFTR-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Sep 15, 2021	The p.G542* pathogenic mutation (also known as c.1624G>T and 1756G>T), located in coding exon 12 of the CFTR gene, results from a G to T substitution at nucleotide position 1624. This changes the amino acid from a glycine to a stop codon within coding exon 12. This mutation, in conjunction with p.F508del, was detected in individuals with pancreatic insufficient cystic fibrosis; it was also identified in conjunction with p.R117H in one individual with pancreatic sufficient cystic fibrosis (Kristidis P et al. Am J Hum Genet. 1992;50(6):1178-1184). This mutation is associated with decreased lung function, elevated sweat chloride levels, and pancreatic insufficiency (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. -
Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 22, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Jul 07, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	Nov 21, 2018	- -
Pathogenic, criteria provided, single submitter	research	HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	Apr 16, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, The Hospital for Sick Children	Oct 02, 2019	- -
Pathogenic, criteria provided, single submitter	research	Center for Precision Medicine, Vanderbilt University Medical Center	Mar 16, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	Nov 05, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 08, 2021	Variant summary: CFTR c.1624G>T (p.Gly542X) 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 0.00034 in 250908 control chromosomes (gnomAD). c.1624G>T has been reported in the literature in multiple individuals affected with Cystic Fibrosis (e.g. McKone_2003, Sosnay_2013). These data indicate that the variant is very likely to be associated with disease. Sixteen ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	curation	CFTR-France	Jan 29, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Oct 18, 2019	NM_000492.3(CFTR):c.1624G>T(G542*) is classified as pathogenic in the context of cystic fibrosis and is associated with the classic form of the disease. Sources cited for classification include the following: PMID 2397487 and 5371902. Classification of NM_000492.3(CFTR):c.1624G>T(G542*) 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. -

not provided Pathogenic:11 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Aug 01, 2022	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
not provided, no classification provided	literature only	SNPedia	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 12, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Feb 11, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Feb 01, 2023	- -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Mar 21, 2023	The CFTR c.1624G>T; p.Gly542Ter variant (rs113993959) has been reported in multiple cystic fibrosis patients, associated with pancreatic insufficiency (Kerem 1990, Castaldo 1997, Loirat 1997, Hirtz 2004, Ooi 2012, Sosnay 2013, CFTR2 database). This variant is reported in ClinVar (Variation ID: 7115), and is found in the general population with an overall allele frequency of 0.03% (91/282312 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. Based on available information, this variant is considered to be pathogenic. References: CFTR2 database: http://cftr2.org/ Castaldo G et al. Severe liver impairment in a cystic fibrosis-affected child homozygous for the G542X mutation. Am J Med Genet. 1997 Mar 17;69(2):155-8. Kerem B et al. Identification of mutations in regions corresponding to the two putative nucleotide (ATP)-binding folds of the cystic fibrosis gene. Proc Natl Acad Sci U S A. 1990 Nov;87(21):8447-51. Loirat F et al. G542X as a probable Phoenician cystic fibrosis mutation. Hum Biol. 1997 Jun;69(3):419-25. Hirtz S et al. CFTR Cl- channel function in native human colon correlates with the genotype and phenotype in cystic fibrosis. Gastroenterology. 2004 Oct;127(4):1085-95. Ooi C and Durie PR. Cystic fibrosis transmembrane conductance regulator (CFTR) gene mutations in pancreatitis. J Cyst Fibros. 2012 Sep;11(5):355-62. Sosnay PR et al. Defining the disease liability of variants in the cystic fibrosis transmembrane conductance regulator gene. Nat Genet. 2013 Oct;45(10):1160-7. -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Dec 24, 2019	he c.1624G>T (p.Gly542*) pathogenic variant (also known as G542X) causes the premature termination of CFTR protein synthesis. It has been reported in individuals affected with cystic fibrosis (CF) and CFTR-related disorders in the published literature (PMIDs: 12767731 (2003), 15371902 (2004), 15994263 (2005), 21416780 (2010), 22658665 (2012), 23751316 (2013), 23951356 (2013)). A functional study has shown that this variant abrogates CFTR chloride channel activity (PMID: 7522901 (1993)). -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	Jul 13, 2022	- -

CFTR-related disorder Pathogenic:3

Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Mar 17, 2017	- -
Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, The Hospital for Sick Children	Oct 02, 2019	- -
Pathogenic, no assertion criteria provided	clinical testing	PreventionGenetics, part of Exact Sciences	Jul 22, 2024	The CFTR c.1624G>T variant is predicted to result in premature protein termination (p.Gly542*). This variant has been documented to cause cystic fibrosis (see for example Kerem et al. 1990. PubMed ID: 2236053; Sosnay et al. 2013. PubMed ID: 23974870). This variant is reported in 0.14% of alleles in individuals of Ashkenazi Jewish descent in gnomAD. Nonsense variants in CFTR are expected to be pathogenic. This variant is interpreted as pathogenic. -

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:2

Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Molecular Genetics and NGS Laboratory, Hospital Fundacion Valle Del Lili	Nov 07, 2023	- -

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

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

-

- -

Bronchiectasis with or without elevated sweat chloride 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Mar 30, 2024

- -

Hereditary pancreatitis Other:1

not provided, no classification provided

literature only

GeneReviews

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.54
CADD	Pathogenic	40
DANN	Uncertain	0.99
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.92
FATHMM_MKL	Uncertain	0.90	D
MutationTaster	Benign	1.0	A;A
Vest4		0.86
GERP RS		5.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.13		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: rs113993959; hg19: chr7-117227832;