7-117534363-G-T

Position:

• chr7-117534363-G-T

Variant summary

Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PVS1 PM2 PP3 PP5_Very_Strong

The NM_000492.4(CFTR):​c.577G>T​(p.Glu193Ter) variant causes a stop gained, splice region change. The variant allele was found at a frequency of 0.00000592 in 1,350,814 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000059 (0 hom.)
• Consequence: CFTR NM_000492.4 stop_gained, splice_region
• Scores: Splicing: ADA: 0.9961
• Clinical Significance: Pathogenic reviewed by expert panel P:10
• Conservation: PhyloP100: 6.93

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 19 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
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.
• PP5: Variant 7-117534363-G-T is Pathogenic according to our data. Variant chr7-117534363-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 54007.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr7-117534363-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.577G>T	p.Glu193Ter	stop_gained, splice_region_variant	5/27	ENST00000003084.11	NP_000483.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CFTR	ENST00000003084.11	c.577G>T	p.Glu193Ter	stop_gained, splice_region_variant	5/27	1	NM_000492.4	ENSP00000003084	P2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000592 AC: 8 AN: 1350814 Hom.: 0 Cov.: 22 AF XY: 0.00000737 AC XY: 5 AN XY: 678696

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: 0.00000791

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000455 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:10

Revision: reviewed by expert panel

Submissions by phenotype

Cystic fibrosis Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Apr 08, 2022	This sequence change creates a premature translational stop signal (p.Glu193*) 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 not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with cystic fibrosis or recurrent pancreatitis (PMID: 22020151, 22658665). ClinVar contains an entry for this variant (Variation ID: 54007). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	curation	CFTR-France	Jan 29, 2018	- -
Pathogenic, reviewed by expert panel	research	CFTR2	Mar 17, 2017	- -
Likely pathogenic, criteria provided, single submitter	literature only	Counsyl	Jan 15, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	May 11, 2022	The p.E193* pathogenic mutation (also known as c.577G>T), located in coding exon 5 of the CFTR gene, results from a G to T substitution at nucleotide position 577. This changes the amino acid from a glutamic acid to a stop codon within coding exon 5. In one study, this mutation was reported in two brothers with a clinical diagnosis of cystic fibrosis and who were pancreatic sufficient and heterozygous for another CFTR mutation (Loubieres Y et al. Chest. 2002; 121(1): 73-80). In another study, this alteration was found in one out of 198 alleles in a cohort of patients with CFTR-related disorders (Amato et al. J Mol Diagn. 2012; 14: 81). This mutation was reported as being associated with elevated sweat chloride, decreased lung function and pancreatic insufficiency (The Clinical and Functional Translation of CFTR (CFTR2); available at http://cftr2.org. Accessed September 15, 2015). 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	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 08, 2020	Variant summary: CFTR c.577G>T (p.Glu193X) 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 250106 control chromosomes. c.577G>T has been reported in the literature in multiple individuals affected with Cystic Fibrosis and CFTR-related disorders (example, Claustres_2000, Dorfman_2010, Ooi_2012, Amato_2012, Loubieres_2002). These data indicate that the variant is very likely to be associated with disease. Four clinical diagnostic laboratories and one 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 (n=4)/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 27, 2017	The CFTR c.577G>T, p.Glu193Ter variant (rs397508759) has been reported in multiple cystic fibrosis patients, and often associated with pancreatic insufficiency (Ooi 2012, Terlizzi 2014, CFTR2 database). It is listed in ClinVar (Variation ID: 54007), but not observed in the general population databases (1000 Genomes Project, Exome Variant Server, Genome Aggregation Database). The variant introduces a premature termination codon, and is predicted to result in a truncated protein or an absent transcript. Based on the above information, the variant is classified as severely pathogenic. References: CFTR2 database: http://cftr2.org/ Ooi C. et al. (2012) Cystic fibrosis transmembrane conductance regulator (CFTR) gene mutations in pancreatitis. J Cyst Fibros. 11(5):355-62. Terlizzi V et al. (2014) Prediction of acute pancreatitis risk based on PIP score in children with cystic fibrosis. J Cyst Fibros. 13(5):579-84. -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 18, 2014	- -

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

Oct 31, 2018

- -

CFTR-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Natera, Inc.

Mar 17, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.65
CADD	Pathogenic	44
DANN	Uncertain	1.0
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.98	D
MutationTaster	Benign	1.0	A;A
Vest4		0.96
GERP RS		5.5

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.81
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

Publications

LitVar

Other links and lift over

dbSNP: rs397508759; hg19: chr7-117174417;