NM_000492.4:c.3587C>G

Variant names:

• chr7-117627640-C-G
• rs121908763
• NM_000492.4:c.3587C>G

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.3587C>G​(p.Ser1196*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,222 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: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: CFTR NM_000492.4 stop_gained
• Clinical Significance: Pathogenic reviewed by expert panel P:10
• Conservation: PhyloP100: 1.35

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]

ENSG00000083622 (HGNC:):

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 7-117627640-C-G is Pathogenic according to our data. Variant chr7-117627640-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 48674.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr7-117627640-C-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CFTR	NM_000492.4	c.3587C>G	p.Ser1196*	stop_gained	Exon 22 of 27	ENST00000003084.11	NP_000483.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CFTR	ENST00000003084.11	c.3587C>G	p.Ser1196*	stop_gained	Exon 22 of 27	1	NM_000492.4	ENSP00000003084.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000799 AC: 2 AN: 250468 Hom.: 0 AF XY: 0.00000739 AC XY: 1 AN XY: 135348

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: 0.0000177

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461222 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 726910

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.: 32

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:10

Revision: reviewed by expert panel

Submissions by phenotype

Cystic fibrosis Pathogenic:6

Jan 29, 2018

CFTR-France

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Jun 24, 2014

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.S1196* pathogenic mutation (also known as c.3587C>G) located in coding exon 22 of the CFTR gene, results from a C to G substitution at nucleotide position 3587. This changes the amino acid from a serine to a stop codon within coding exon 22. This pathogenic mutation was first identified in a Russian patient with cystic fibrosis; however, the second alteration and clinical information was not provided (Ivaschenko TE et al. Hum Genet. 1993;91(1):63-5). This pathogenic mutation is associated with pancreatic insufficiency (PI), elevated sweat chloride levels, and higher rate of Pseudomonas infection (Sosnay PR et al. Nat Genet. 2013;45(10):1160-1167, Supplementary Table and The Clinical and Functional Translation of CFTR (CFTR2); available at http://cftr2.org. Accessed June 23, 2014). In addition, since premature stop codons are typically deleterious in nature, this alteration is interpreted as a disease-causing mutation (ACMG Recommendations for Standards for Interpretation and Reporting of Sequence Variations. Revision 2007. Genet Med. 2008;10:294). -

Dec 04, 2019

Myriad Genetics, Inc.

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

NM_000492.3(CFTR):c.3587C>G(S1196*) is classified as pathogenic in the context of cystic fibrosis. Sources cited for classification include the following: PMID 23276700, 16051530, 12624947, 7541274, 8889582, 23974870, 12007216, 7681034, 18456578 and 18373402. Classification of NM_000492.3(CFTR):c.3587C>G(S1196*) 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. -

Feb 27, 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.3587C>G (p.Ser1196X) 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 allele was found at a frequency of 8e-06 in 250468 control chromosomes. c.3587C>G 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. One clinical diagnostic laboratory, one expert panel (CFTR2) and a database (CFTR-France) 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. -

Mar 17, 2017

CFTR2

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: research

- -

May 08, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This premature translational stop signal has been observed in individual(s) with cystic fibrosis (PMID: 7681034, 32429104). ClinVar contains an entry for this variant (Variation ID: 48674). For these reasons, this variant has been classified as Pathogenic. This variant is present in population databases (rs121908763, gnomAD 0.002%). This sequence change creates a premature translational stop signal (p.Ser1196*) 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). -

CFTR-related disorder Pathogenic:1

Mar 17, 2017

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Pathogenic:1

Sep 19, 2024

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The CFTR c.3587C>G (p.Ser1196*) variant causes the premature termination of CFTR protein synthesis. This variant has been reported in the published literature in affected individuals with cystic fibrosis (PMIDs: 23276700 (2013), 18456578 (2008), 1837340 (2008), 16051530 (2005), 8889582 (1996), 7681034 (1993), and 7541274 (1995)). It has also been reported in individuals with cystic fibrosis and congenital bilateral absence of the vas deferens (PMID: 38003474 (2023)). In addition, it is associated with pancreatic insufficiency, elevated sweat chloride levels, and a higher rate of pseudomonas infection (PMID: 23974870 (2013)). The frequency of this variant in the general population, 0.0044 (13/2922 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with pathogenicity. Based on the available information, this variant is classified 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:1

Jan 04, 2022

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

Sep 10, 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	0.61	D
BayesDel_noAF	Uncertain	0.10
CADD	Pathogenic	34
DANN	Benign	0.90
Eigen	Benign	-0.11
Eigen_PC	Benign	-0.44
FATHMM_MKL	Benign	0.055	N
Vest4		0.87
ClinPred		0.53	D
GERP RS		0.91

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

Publications

LitVar

Other links and lift over

dbSNP: rs121908763; hg19: chr7-117267694;