rs121909006

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. The variant received 17 ACMG points: 17P and 0B. PM1PM5PP2PP3_StrongPP5_Very_Strong

The NM_000492.4(CFTR):c.1687T>A(p.Tyr563Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000624 in 1,603,020 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 (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y563D) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000062 ( 0 hom. )

Consequence

CFTR
NM_000492.4 missense

Scores

Clinical Significance

Pathogenic reviewed by expert panel P:16

Conservation

PhyloP100: 7.41

Publications

14 publications found

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 Gene-Disease associations (from GenCC):

cystic fibrosis
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), Myriad Women’s Health, Orphanet
congenital bilateral absence of vas deferens
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
hereditary chronic pancreatitis
Inheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

CFTR links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 17 ACMG points.

PM1

In a hotspot region, there are 16 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 18 uncertain in NM_000492.4

PM5

Other missense variant is known to change same aminoacid residue: Variant chr7-117590360-T-G is described in ClinVar as Pathogenic. ClinVar VariationId is 53342.Status of the report is reviewed_by_expert_panel, 3 stars.

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 197 curated pathogenic missense variants (we use a threshold of 10). The gene has 46 curated benign missense variants. Gene score misZ: -3.1397 (below the threshold of 3.09). Trascript score misZ: -1.0868 (below the threshold of 3.09). GenCC associations: The gene is linked to hereditary chronic pancreatitis, cystic fibrosis, congenital bilateral absence of vas deferens.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.992

PP5

Variant 7-117590360-T-A is Pathogenic according to our data. Variant chr7-117590360-T-A is described in ClinVar as Pathogenic. ClinVar VariationId is 7114.Status of the report is reviewed_by_expert_panel, 3 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CFTR	NM_000492.4 link	c.1687T>A	p.Tyr563Asn	missense_variant	Exon 13 of 27	ENST00000003084.11	NP_000483.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CFTR	ENST00000003084.11 link	c.1687T>A	p.Tyr563Asn	missense_variant	Exon 13 of 27	1	NM_000492.4	ENSP00000003084.6

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

152082

Hom.:

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.00000799

AC:

AN:

250432

AF XY:

0.00000738

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000177

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000620

AC:

AN:

1450938

Hom.:

Cov.:

AF XY:

0.00000277

AC XY:

AN XY:

721598

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33232

American (AMR)

AF:

0.00

AC:

AN:

44398

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25622

East Asian (EAS)

AF:

0.00

AC:

AN:

39370

South Asian (SAS)

AF:

0.00

AC:

AN:

86100

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52600

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5686

European-Non Finnish (NFE)

AF:

0.00000724

AC:

AN:

1104266

Other (OTH)

AF:

0.0000168

AC:

AN:

59664

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.436

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00000658

AC:

AN:

152082

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74292

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41458

American (AMR)

AF:

0.00

AC:

AN:

15268

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5204

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

67918

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:16

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Cystic fibrosis

Pathogenic:9

Dec 08, 2017

CFTR2

Significance:Pathogenic

Review Status:reviewed by expert panel

Collection Method:research

Jan 04, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The CFTR c.1687T>A; p.Tyr563Asn variant (rs121909006) is reported in multiple individuals with cystic fibrosis who have an average sweat chloride of 95mEq/L, and is commonly associated with pancreatic insufficiency (CFTR2 database, Fichou 2008). This variant is also reported in ClinVar (Variation ID: 7114). It is only found on two alleles in the Genome Aggregation Database (v2.1.1), indicating it is not a common polymorphism. Computational analyses predict that this variant is deleterious (REVEL: 0.969). In support of these predictions, functional analysis of the variant protein demonstrated 1.9% of wild type chloride conductance activity (CFTR database, Raraigh 2018). Based on available information, this variant is considered to be pathogenic. References: Link to CFTR2 database: cftr2.org/ Fichou Y et al. Estimating the age of CFTR mutations predominantly found in Brittany (Western France). J Cyst Fibros. 2008 Mar;7(2):168-73. PMID: 17825628. Raraigh KS et al. Functional Assays Are Essential for Interpretation of Missense Variants Associated with Variable Expressivity. Am J Hum Genet. 2018 Jun 7;102(6):1062-1077. PMID: 29805046.

Jun 13, 2022

Ambry Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.Y563N pathogenic mutation (also known as c.1687T>A), located in coding exon 13 of the CFTR gene, results from a T to A substitution at nucleotide position 1687. The tyrosine at codon 563 is replaced by asparagine, an amino acid with dissimilar properties. This mutation was observed in a pancreatic sufficient individual with cystic fibrosis (CF) who was also heterozygous for a nonsense alteration; however, phase (cis or trans) was not determined (Kerem BS et al. Proc. Natl. Acad. Sci. U.S.A., 1990 Nov;87:8447-51). In another study, this mutation was observed in trans with a nonsense alteration in an individual with CF (Fichou Y et al. J. Cyst. Fibros., 2008 Mar;7:168-73). In vitro expression analysis revealed that the p.Y563N mutation results in decreased levels of mature CFTR protein (Van Oene M et al. J. Biol. Chem., 2000 Jun;275:19577-84). Based on the available evidence, the p.Y563N is classified as a pathogenic mutation.

Jan 22, 2018

Counsyl

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com.

Nov 01, 1990

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

Aug 04, 2022

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.1687T>A (p.Tyr563Asn) results in a non-conservative amino acid change located in the ABC transporter-like, ATP-binding domain (IPR003439) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 250432 control chromosomes. c.1687T>A has been reported in the literature in multiple individuals affected with Cystic Fibrosis (example, McCague_2019). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <1% of normal CFTR activity in vitro (example, Han_2018). Multiple clinical diagnostic laboratories and an 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. Based on the evidence outlined above, the variant was classified as pathogenic.

Jun 12, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces tyrosine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 563 of the CFTR protein (p.Tyr563Asn). This variant is present in population databases (rs121909006, gnomAD 0.0009%). This missense change has been observed in individual(s) with cystic fibrosis (PMID: 1376017, 2236053, 10923036, 12815607, 15858154, 17825628; Invitae). 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: 7114). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt CFTR protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects CFTR function (PMID: 10764788). 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

Feb 29, 2024

Johns Hopkins Genomics, Johns Hopkins University

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Disease-causing CFTR variant. See www.CFTR2.org for phenotype information.

not provided

Pathogenic:2

Nov 07, 2023

Mayo Clinic Laboratories, Mayo Clinic

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PP3, PP5, PM2_strong, PS1, PS3

Dec 20, 2023

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Published functional studies demonstrate a damaging effect on protein expression and function (PMID: 29805046, 10764788, 30046002); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 28603918, 30046002, 18361776, 10764788, 25489051, 17825628, 8956039, 1376017, 12815607, 10923036, 15858154, 1376016, 2236053, 34782259, 30888834, 28068001, 29805046)

CFTR-related disorder

Pathogenic:1

Aug 22, 2024

PreventionGenetics, part of Exact Sciences

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

The CFTR c.1687T>A variant is predicted to result in the amino acid substitution p.Tyr563Asn. This variant has been widely reported to be pathogenic for cystic fibrosis due to significantly decreased levels of mature CFTR protein (see for example, Kerem et al. 1990. PubMed ID: 2236053; Masica et al. 2015. PubMed ID: 25489051; Raraigh et al. 2018. PubMed ID: 29805046). This variant is reported in 0.0018% of alleles in individuals of European (Non-Finnish) descent in gnomAD. All submitters classified the variant as pathogenic in the ClinVar database (https://preview.ncbi.nlm.nih.gov/clinvar/variation/7114/). This variant is interpreted as pathogenic.

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

Pathogenic:1

Baylor Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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 20, 2024

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

Nov 22, 2023

Baylor Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Cystic fibrosis;C5924204:CFTR-related disorder

Pathogenic:1

Mar 09, 2018

CFTR-France

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:curation

the variant causes a phenotype but regarding our data, we can't formally attribute it to CF, CFTR-RD or both

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.96

BayesDel_addAF

Pathogenic

0.50

BayesDel_noAF

Pathogenic

0.48

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.98

D;.;D;.

Eigen

Pathogenic

0.81

Eigen_PC

Pathogenic

0.73

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

1.0

D;D;D;D

M_CAP

Pathogenic

0.71

MetaRNN

Pathogenic

0.99

D;D;D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Uncertain

2.9

M;.;.;.

PhyloP100

7.4

PrimateAI

Pathogenic

0.84

PROVEAN

Pathogenic

-8.2

D;.;D;.

REVEL

Pathogenic

0.97

Sift

Pathogenic

0.0

D;.;D;.

Sift4G

Uncertain

0.0050

D;.;D;.

Vest4

1.0

ClinPred

1.0

GERP RS

4.8

Varity_R

1.0

gMVP

0.98

Mutation Taster

=2/98

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

Splicevardb

2.0

SpliceAI score (max)

0.030

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over