rs141482808

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PM1PP2PP3_ModeratePP5_Very_Strong

The NM_000492.4(CFTR):c.571T>G(p.Phe191Val) variant causes a missense change. The variant allele was found at a frequency of 0.0000182 in 1,536,306 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 (★★★).

Frequency

Genomes: 𝑓 0.000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000013 ( 0 hom. )

Consequence

CFTR
NM_000492.4 missense

Scores

Clinical Significance

Pathogenic reviewed by expert panel P:16U:1

Conservation

PhyloP100: 5.37

Publications

8 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 13 ACMG points.

PM1

In a hotspot region, there are 10 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 30 uncertain in NM_000492.4

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, 0.899

PP5

Variant 7-117534357-T-G is Pathogenic according to our data. Variant chr7-117534357-T-G is described in ClinVar as Pathogenic. ClinVar VariationId is 495953.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.571T>G	p.Phe191Val	missense_variant	Exon 5 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.571T>G	p.Phe191Val	missense_variant	Exon 5 of 27	1	NM_000492.4	ENSP00000003084.6

Frequencies

GnomAD3 genomes

AF:

0.0000657

AC:

AN:

152184

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000193

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000120

AC:

AN:

250352

AF XY:

0.00000738

show subpopulations

Gnomad AFR exome

AF:

0.000185

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000130

AC:

AN:

1384122

Hom.:

Cov.:

AF XY:

0.00000721

AC XY:

AN XY:

693418

show subpopulations

African (AFR)

AF:

0.000439

AC:

AN:

31910

American (AMR)

AF:

0.0000224

AC:

AN:

44604

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25628

East Asian (EAS)

AF:

0.00

AC:

AN:

39298

South Asian (SAS)

AF:

0.00

AC:

AN:

84636

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52778

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5626

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1041720

Other (OTH)

AF:

0.0000518

AC:

AN:

57922

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

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:

0.0000657

AC:

AN:

152184

Hom.:

Cov.:

AF XY:

0.0000807

AC XY:

AN XY:

74350

show subpopulations

African (AFR)

AF:

0.000193

AC:

AN:

41454

American (AMR)

AF:

0.000131

AC:

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5198

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68028

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.540

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.0000636

Hom.:

Bravo

AF:

0.000121

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:16Uncertain:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Cystic fibrosis

Pathogenic:6Uncertain:1

Jul 22, 2021

Genome-Nilou Lab

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

May 20, 2022

Mendelics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Jan 10, 2020

CFTR2

Significance:Pathogenic

Review Status:reviewed by expert panel

Collection Method:research

Dec 12, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces phenylalanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 191 of the CFTR protein (p.Phe191Val). This variant is present in population databases (rs141482808, gnomAD 0.01%). This missense change has been observed in individual(s) with clinical features of cystic fibrosis (PMID: 12167682, 18500736, 26708955). ClinVar contains an entry for this variant (Variation ID: 495953). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

Feb 13, 2025

Ambry Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.F191V variant (also known as c.571T>G), located in coding exon 5 of the CFTR gene, results from a T to G substitution at nucleotide position 571. The phenylalanine at codon 191 is replaced by valine, an amino acid with highly similar properties. This alteration has been identified in multiple individuals diagnosed with non-classic cystic fibrosis in conjunction with other pathogenic mutations; however, the phase of these alterations was not provided (Groman JD et al. N. Engl. J. Med., 2002 Aug;347:401-7; McCravy MS et al. Eur Respir J, 2020 Jul;56:). This variant was also identified in the homozygous state in an African American newborn with cystic fibrosis and elevated sweat chloride levels (Giusti R et al. Pediatr. Pulmonol., 2008 Jul;43:638-41). 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 02/13/2025). This variant has <10% of wild type quantity and function in The Clinical and Functional TRanslation of CFTR (CFTR2) database (available at http://cftr2.org. Accessed 02/13/2025). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.

Nov 25, 2024

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.571T>G (p.Phe191Val) results in a non-conservative amino acid change located in the ABC transporter type 1, transmembrane domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 250352 control chromosomes. c.571T>G has been reported in the literature in individuals with features of cystic fibrosis in the presumed compound heterozygous state with other pathogenic variants (e.g. Groman_2002, Krasnov_2008, McCravy_2020, Gonska_2021, Cornet_2023). It has also been reported as a homozygous genotype in an African-American infant diagnosed with Cystic Fibrosis by newborn screening (NBS) (Giusti_2008). These data indicate that the variant is likely to be associated with disease. Experimental evidence evaluating an impact on protein function suggests the variant disrupts expression of the mature protein and ion transport, which can be corrected by drug treatment and results in approximately 4.58% of normal chloride channel conductance relative to wild type (McCravy_2020, Bihler_2024). The following publications have been ascertained in the context of this evaluation (PMID: 38388235, 36751320, 18500736, 34814176, 12167682, 18951463, 32265312, 31845523, 35527187, 34583889, 26708955). ClinVar contains an entry for this variant (Variation ID: 495953). Based on the evidence outlined above, the variant was classified as pathogenic.

Mar 30, 2020

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not provided

Pathogenic:3

Apr 06, 2023

GeneDx

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Published functional studies suggest a damaging effect: decreased protein expression and reduced channel activity (McCravy 2020); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 12167682, 26708955, 31845523, 32265312, 18951463, 34996830, 35527187, 34583889, 35451201, 36751320, 18500736)

Apr 21, 2017

Eurofins Ntd Llc (ga)

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Aug 03, 2022

Mayo Clinic Laboratories, Mayo Clinic

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PP3, PM3_strong, PS3

CFTR-related disorder

Pathogenic:2

Mar 07, 2024

PreventionGenetics, part of Exact Sciences

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

The CFTR c.571T>G variant is predicted to result in the amino acid substitution p.Phe191Val. This variant has been reported in individuals with classic and non-classic cystic fibrosis (Groman et al. 2002. PubMed ID: 12167682; Schrijver et al. 2016. PubMed ID: 26708955; Gunnett et al. 2023. PubMed ID: 36969284). Additionally, this variant has been reported compound heterozygous with another pathogenic variant in a patient with cystic fibrosis (Cornet et al. 2022. PubMed ID: 36751320). In vitro, and in vivo functional and biochemical studies using human nasal epithelial cells demonstrated diminished protein expression and reduced ion transport which improved with combination therapy treatment (McCravy et al. 2020. PubMed ID: 32265312). This variant is reported in 0.019% of alleles in individuals of African descent in gnomAD. This variant is interpreted as pathogenic.

Mar 30, 2020

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

not specified

Pathogenic:1

Feb 21, 2019

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The CFTR c.571T>G; p.Phe191Val variant (rs141482808) is reported in the literature in individuals affected with cystic fibrosis (CF) or nonclassic CF (Giusti 2008, Groman 2002, Schrijver 2016). This variant has been observed in the homozygous state in a newborn with a positive sweat chloride test (Giusti 2008) and in an individual with nonclassic CF that carried an additional pathogenic CFTR variant (Groman 2002). Similarly, in testing performed at ARUP Laboratories, the p.Phe191Val variant has been observed in an individual with elevated sweat chloride that carried a second pathogenic variant. The p.Phe191Val variant is found on only three chromosomes (3/16210 alleles, 0.02%) in the African population in the Genome Aggregation Database, indicating it is not a common polymorphism. The phenylalanine at codon 191 is moderately conserved, but computational analyses (SIFT: tolerated, PolyPhen-2: damaging) predict conflicting effects of this variant on protein structure/function. However, based on available information, including its incidence in affected individuals, this variant is considered to be likely pathogenic. References: Giusti R et al. Elevated IRT levels in African-American infants: implications for newborn screening in an ethnically diverse population. Pediatr Pulmonol. 2008 Jul;43(7):638-41. Groman JD et al. Variant cystic fibrosis phenotypes in the absence of CFTR mutations. N Engl J Med. 2002 Aug 8;347(6):401-7. Schrijver I et al. The Spectrum of CFTR Variants in Nonwhite Cystic Fibrosis Patients: Implications for Molecular Diagnostic Testing. J Mol Diagn. 2016 Jan;18(1):39-50.

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

Pathogenic:1

Baylor Genetics

Significance:Likely 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

Apr 13, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Bronchiectasis with or without elevated sweat chloride 1

Pathogenic:1

Mar 17, 2024

Baylor Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Cystic fibrosis;C5924204:CFTR-related disorder

Pathogenic:1

Jan 18, 2021

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

0.59

BayesDel_addAF

Pathogenic

0.21

BayesDel_noAF

Pathogenic

0.30

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.83

D;.;.;.

Eigen

Pathogenic

0.72

Eigen_PC

Pathogenic

0.70

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.95

D;D;D;D

M_CAP

Pathogenic

0.82

MetaRNN

Pathogenic

0.90

D;D;D;D

MetaSVM

Uncertain

0.73

MutationAssessor

Uncertain

2.8

M;.;.;M

PhyloP100

5.4

PrimateAI

Uncertain

0.77

PROVEAN

Uncertain

-2.6

D;.;.;.

REVEL

Pathogenic

0.89

Sift

Benign

0.081

T;.;.;.

Sift4G

Uncertain

0.0050

D;.;.;.

Vest4

0.89

ClinPred

0.97

GERP RS

5.5

Varity_R

0.94

gMVP

0.83

Mutation Taster

=7/93

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

Splicevardb

3.0

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over