chr7-117534357-T-G

Position:

chr7-117534357-T-G

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1PM2PP3_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:15U:1

Conservation

PhyloP100: 5.37

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 14 ACMG points.

PM1

In a domain ABC transmembrane type-1 1 (size 284) in uniprot entity CFTR_HUMAN there are 65 pathogenic changes around while only 10 benign (87%) in NM_000492.4

PM2

Very rare variant in population databases, with high coverage;

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 id is 495953.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr7-117534357-T-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CFTR	NM_000492.4 linkuse as main transcript	c.571T>G	p.Phe191Val	missense_variant	5/27	ENST00000003084.11	NP_000483.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CFTR	ENST00000003084.11 linkuse as main transcript	c.571T>G	p.Phe191Val	missense_variant	5/27	1	NM_000492.4	ENSP00000003084	P2	P13569-1

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

GnomAD3 exomes

AF:

0.0000120

AC:

AN:

250352

Hom.:

AF XY:

0.00000738

AC XY:

AN XY:

135416

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 SAS 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

Gnomad4 AFR exome

AF:

0.000439

Gnomad4 AMR exome

AF:

0.0000224

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:

0.00

Gnomad4 OTH exome

AF:

0.0000518

GnomAD4 genome

AF:

0.0000657

AC:

AN:

152184

Hom.:

Cov.:

AF XY:

0.0000807

AC XY:

AN XY:

74350

show subpopulations

Gnomad4 AFR

AF:

0.000193

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

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:15Uncertain:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Cystic fibrosis

Pathogenic:6Uncertain:1

Pathogenic, reviewed by expert panel	research	CFTR2	Jan 10, 2020	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 22, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 20, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 12, 2021	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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 09, 2023	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 (gnomAD). 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). The variant continues to be cited by others in relation to the presence of FDA-approved treatments and its presence as a CF-causing variant in the CFTR2 database (e.g. Raraigh_2022). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function, suggesting the variant disrupts expression of the mature protein and ion transport, which can be corrected by drug treatment (McCravy_2020). The following publications have been ascertained in the context of this evaluation (PMID: 12167682, 18951463, 18500736, 26708955, 31845523, 34583889, 35527187, 34814176, 36751320, 32265312). Ten submitters, including an expert panel, have cited clinical-significance assessments for this variant to ClinVar after 2014, and classified it as pathogenic (n=3, including a CFTR2 expert panel), likely pathogenic (n=6), or uncertain significance (n=1). Based on the evidence outlined above, the variant was classified as likely pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Jul 18, 2023	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 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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, The Hospital for Sick Children	Mar 30, 2020	- -

not provided

Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 21, 2017	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 06, 2023	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) -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Aug 03, 2022	PP3, PM3_strong, PS3 -

CFTR-related disorder

Pathogenic:2

Pathogenic, no assertion criteria provided	clinical testing	PreventionGenetics, part of Exact Sciences	Mar 07, 2024	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. -
Likely pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, The Hospital for Sick Children	Mar 30, 2020	- -

not specified

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Feb 21, 2019

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;na:CFTR-related disorder

Pathogenic:1

Pathogenic, criteria provided, single submitter

curation

CFTR-France

Jan 18, 2021

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

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

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

- -

Bronchiectasis with or without elevated sweat chloride 1

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Mar 17, 2024

- -

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

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

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.77

PROVEAN

Uncertain

-2.6

D;.;.;.

REVEL

Pathogenic

0.89

Sift

Benign

0.081

T;.;.;.

Sift4G

Uncertain

0.0050

D;.;.;.

Polyphen

0.95

P;.;.;.

Vest4

0.89

MVP

0.99

MPC

0.015

ClinPred

0.97

GERP RS

5.5

Varity_R

0.94

gMVP

0.83

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

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