dbSNP rs397508675: CFTR:p.Glu1371* (chr7-117664835-G-T) – ACMG Classification: Pathogenic (18 pts)

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_000492.4(CFTR):c.4111G>T(p.Glu1371*) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,716 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: not found (cov: 33)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

CFTR
NM_000492.4 stop_gained

Scores

Clinical Significance

Pathogenic reviewed by expert panel P:7

Conservation

PhyloP100: 9.40

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 7-117664835-G-T is Pathogenic according to our data. Variant chr7-117664835-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 53891.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr7-117664835-G-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CFTR	NM_000492.4 link	c.4111G>T	p.Glu1371*	stop_gained	Exon 25 of 27	ENST00000003084.11	NP_000483.3	P13569-1A0A024R730

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CFTR	ENST00000003084.11 link	c.4111G>T	p.Glu1371*	stop_gained	Exon 25 of 27	1	NM_000492.4	ENSP00000003084.6		P13569-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251252

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135780

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:

0.00000881

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000205

AC:

AN:

1461716

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727176

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:

0.00000270

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000756

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Cystic fibrosis

Pathogenic:5

Mar 17, 2017

CFTR2

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: research

- -

Sep 21, 2021

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.E1371* pathogenic mutation (also known as c.4111G>T), located in coding exon 25 of the CFTR gene, results from a G to T substitution at nucleotide position 4111. This changes the amino acid from a glutamic acid to a stop codon within coding exon 25. This mutation was first identified in a 35-year-old Caucasian patient with severe pulmonary disease and pancreatic insufficiency, who was compound heterozygous for deltaF508 (Cutting GR, Am. J. Hum. Genet. 1992 Jun; 50(6):1185-94). It was later reportedly identified on one cystic fibrosis (CF) chromosome in a study of Northern Irish CF families (Hughes DJ, Hum. Mutat. 1996 ; 8(4):340-7). In addition, it was detected as compound heterozygous with another disease-causing mutation in an individual with pancreatic-sufficient cystic fibrosis and acute recurrent pancreatitis (St Onge I et al. J Cyst Fibros, 2019 09;18:e53-e55). This variant has been reported in multiple individuals with an elevated sweat chloride level in The Clinical and Functional TRanslation of CFTR (CFTR2) database (available at http://cftr2.org. Accessed 09/21/2021). 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. -

Nov 18, 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.Glu1371*) 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 (rs397508675, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with cystic fibrosis (PMID: 1376017). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 53891). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

Sep 16, 2020

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Dec 22, 2014

Counsyl

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: literature only

- -

not specified

Pathogenic:1

Apr 06, 2018

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.4111G>T (p.Glu1371X) 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 (eg.c.4144C>T/p.Gln1382X). The variant allele was found at a frequency of 4.1e-06 in 246000 control chromosomes. c.4111G>T has been reported in the literature in individuals affected with Cystic Fibrosis. These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar and classified the variant as likely pathogenic. CFTR2 database lists variant as a CF-causing variant with 19 patients with this variant in the database. Based on the evidence outlined above, the variant was classified as pathogenic. -

not provided

Pathogenic:1

Jun 28, 2021

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. It has been reported in individuals affected with Cystic Fibrosis in the published literature (PMID: 8956039 (1996), 31036917 (2019), 1376017 (1992)). In addition, this variant has been reported to have a damaging effect on CFTR protein function (PMID: 30444886 (2018)). Based on the available information, this variant is classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.63

BayesDel_noAF

Pathogenic

0.66

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Pathogenic

1.3

Eigen_PC

Pathogenic

1.2

FATHMM_MKL

Pathogenic

0.99

Vest4

0.96

GERP RS

5.9

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.27

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.27

Position offset: 25

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