rs77101217

chr7-117559548-C-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.1477C>T(p.Gln493Ter) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000059 in 1,611,422 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 (★★★). Synonymous variant affecting the same amino acid position (i.e. Q493Q) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000064 (0 hom.)
• Consequence: CFTR NM_000492.4 stop_gained
• Clinical Significance: Pathogenic reviewed by expert panel P:19 O:1
• Conservation: PhyloP100: 7.44

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-AS1 (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 7-117559548-C-T is Pathogenic according to our data. Variant chr7-117559548-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 7107.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr7-117559548-C-T is described in Lovd as [Pathogenic]. Variant chr7-117559548-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CFTR	NM_000492.4	c.1477C>T	p.Gln493Ter	stop_gained	11/27	ENST00000003084.11
CFTR-AS1	NR_149084.1	n.221+1185G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CFTR	ENST00000003084.11	c.1477C>T	p.Gln493Ter	stop_gained	11/27	1	NM_000492.4	P2

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152104 Hom.: 0 Cov.: 32

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000199 AC: 5 AN: 251326 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135838

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: 0.0000440

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000644 AC: 94 AN: 1459318 Hom.: 0 Cov.: 30 AF XY: 0.0000510 AC XY: 37 AN XY: 726132

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: 0.0000838

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152104 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74300

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000667 Hom.: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.0000165 AC: 2

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:19 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Cystic fibrosis Pathogenic:10 Other:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Nov 01, 1990	- -
Pathogenic, reviewed by expert panel	research	CFTR2	Mar 17, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Johns Hopkins Genomics, Johns Hopkins University	Apr 22, 2020	Disease-causing CFTR variant. See www.CFTR2.org for phenotype information. -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Nov 11, 2019	NM_000492.3(CFTR):c.1477C>T(Q493*) is classified as pathogenic in the context of cystic fibrosis and is associated with the classic form of disease. Sources cited for classification include the following: PMID 23974870 and 18456578. Classification of NM_000492.3(CFTR):c.1477C>T(Q493*) 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.‚Äã -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 26, 2024	This sequence change creates a premature translational stop signal (p.Gln493*) 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 (rs77101217, gnomAD 0.005%). This premature translational stop signal has been observed in individual(s) with cystic fibrosis (PMID: 1376016, 2236053, 12815607, 21184098, 21858268, 23974870). ClinVar contains an entry for this variant (Variation ID: 7107). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	curation	CFTR-France	Jan 29, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Jun 13, 2022	The p.Q493* pathogenic mutation (also known as c.1477C>T), located in coding exon 11 of the CFTR gene, results from a C to T substitution at nucleotide position 1477. This changes the amino acid from a glutamine to a stop codon within coding exon 11. This mutation was originally described in an individual with cystic fibrosis (clinical criteria were not provided) and pancreatic insufficiency (Kerem BS et al. Proc. Natl. Acad. Sci. U.S.A., 1990 Nov;87:8447-51). This mutation was also observed in conjunction with the (TG)12-5T variant in a male with congenital bilateral absence of the vas deferens (CBAVD); however, phase was not determined (Steiner B et al. Hum. Mutat., 2011 Aug;32:912-20). This mutation is associated with pancreatic insufficiency, pulmonary disease, and elevated sweat chloride levels (Sosnay PR et al. Nat. Genet., 2013 Oct;45:1160-7). 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	Apr 14, 2016	Variant summary: The variant of interest causes a nonsense change involving a conserved nucleotide resulting in a predicted truncated CFTR protein, a known mechanism for disease. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 2/121326 (1/60663), which does not exceed the predicted maximum expected allele frequency for a pathogenic CFTR variant of 1/77. The variant of interest has been reported in multiple affected individuals via publications, along with multiple reputable clinical laboratories/databases cite the variant as "pathogenic." Therefore, taking all available lines of evidence into consideration, the variant of interest is classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Aug 15, 2017	The CFTR c.1477C>T (p.Gln493Ter) stop-gained variant has been reported in at least four studies and is found in a total of six affected individuals including four compound heterozygotes, one complex heterozygote, and one presumed heterozygote (Kerem et al. 1990; Kristidis et al. 1992; Feuillet-Fieux et al. 2011; Steiner et al. 2011). Three of the compound heterozygotes have a clinical diagnosis of cystic fibrosis and pancreatic insufficiency and have the p.Phe508del variant as their second variant (Kristidis et al. 1992). Steiner et al. (2011) reported on a compound heterozygote with a diagnosis of congenital bilateral absence of the vas deferens. Feuillet-Fieux et al. (2011) identified a complex heterozygous individual, with a clinical diagnosis of cystic fibrosis based on sweat chloride values who had no other pulmonary or intestinal symptoms, who carried three other variants on the maternal allele and the p.Gln493Ter variant on the paternal allele. The p.Gln493Ter variant was absent from 2456 controls and is reported at a frequency of 0.000047 in the European (non-Finnish) population of the Genome Aggregation Database. Due to the potential impact of stop-gained variants and the evidence available, the p.Gln493Ter 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	Baylor Genetics	Feb 19, 2021	- -
not provided, no classification provided	phenotyping only	GenomeConnect, ClinGen	-	Variant interpreted as Pathogenic and reported on 09-23-2020 by Lab or GTR ID 500068. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -

not provided Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 10, 2023	The CFTR c.1477C>T; p.Gln493Ter variant (rs77101217) has been reported in cystic fibrosis patients, often associated with pancreatic insufficiency (CFTR2 database, Kerem 1990, Ooi 2012, Sosnay 2013). This variant is also reported in ClinVar (Variation ID: 7107). It is only found on six alleles in the Genome Aggregation Database (v2.1.1), indicating it is not a common polymorphism. 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/ Kerem BS 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. PMID: 2236053. Ooi CY et al. Cystic fibrosis transmembrane conductance regulator (CFTR) gene mutations in pancreatitis. J Cyst Fibros. 2012 Sep;11(5):355-62. PMID: 22658665. 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. PMID: 23974870. -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Apr 08, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 15, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Aug 10, 2022	- -

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

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

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- -

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

Feb 14, 2022

- -

CFTR-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Natera, Inc.

Mar 17, 2017

- -

Bronchiectasis with or without elevated sweat chloride 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Oct 23, 2023

- -

Congenital bilateral aplasia of vas deferens from CFTR mutation Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

MGZ Medical Genetics Center

Dec 23, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.53	D
BayesDel_noAF	Pathogenic	0.66
Cadd	Pathogenic	40
Dann	Uncertain	1.0
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	1.1
FATHMM_MKL	Pathogenic	0.98	D
MutationTaster	Benign	1.0	A;A
Vest4		0.97
GERP RS		5.5

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs77101217; hg19: chr7-117199602;