rs139304906

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1PM2PP3_ModeratePP5_Very_Strong

The NM_000492.4(CFTR):c.3230T>C(p.Leu1077Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000031 in 1,613,514 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/20 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

CFTR
NM_000492.4 missense

Scores

Clinical Significance

Pathogenic reviewed by expert panel P:15

Conservation

PhyloP100: 7.93

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:

(HGNC:):

links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PM1

In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 uncertain in NM_000492.4

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.865

PP5

Variant 7-117611671-T-C is Pathogenic according to our data. Variant chr7-117611671-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 53690.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr7-117611671-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CFTR	NM_000492.4 linkuse as main transcript	c.3230T>C	p.Leu1077Pro	missense_variant	20/27	ENST00000003084.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CFTR	ENST00000003084.11 linkuse as main transcript	c.3230T>C	p.Leu1077Pro	missense_variant	20/27	1	NM_000492.4	P2	P13569-1
	ENST00000456270.1 linkuse as main transcript	n.177+4558A>G		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152108

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

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251086

Hom.:

AF XY:

0.00000737

AC XY:

AN XY:

135688

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 SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000881

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000274

AC:

AN:

1461406

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

727008

show subpopulations

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:

0.0000166

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152108

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74300

show subpopulations

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:

0.0000337

Hom.:

Bravo

AF:

0.00000756

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.0000546

EpiControl

AF:

0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:15

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Cystic fibrosis

Pathogenic:10

Pathogenic, criteria provided, single submitter	curation	CFTR-France	Jan 29, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Jul 18, 2022	The p.L1077P pathogenic mutation (also known as c.3230T>C), located in coding exon 20 of the CFTR gene, results from a T to C substitution at nucleotide position 3230. The leucine at codon 1077 is replaced by proline, an amino acid with similar properties. In one study, this mutation was identified in one individual with cystic fibrosis in conjunction with p.F508del (Bozon D et al. Hum. Mutat., 1994;3:330-2). In another study, this mutation was seen in 4 individuals with cystic fibrosis in conjunction with a second pathogenic mutation (Parisi GF et al. BMC Res Notes, 2013 Nov;6:461). This mutation is associated with elevated sweat chloride levels and pancreatic insufficiency; in vitro functional studies showed this mutation results in no to very little chloride conductance (Sosnay PR et al. Nat. Genet., 2013 Oct;45:1160-7). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -
Pathogenic, reviewed by expert panel	research	CFTR2	Mar 17, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	Nov 05, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 30, 2016	Variant summary: The CFTR c.3230T>C (p.Leu1077Pro) variant involves the alteration of a conserved nucleotide. 5/5 in silico tools predict a damaging outcome for this variant. This variant was found in 1/120564 control chromosomes at a frequency of 0.0000083, which does not exceed the estimated maximal expected allele frequency of a pathogenic CFTR variant (0.0129603). The variant has been reported in numerous affected individuals in the literature and has been shown via in vitro functional studies to result in the complete loss of chloride transport/conduction (Van Goor_2013, Sosnay_2013). In addition, one clinical diagnostic laboratory/reputable database has classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Counsyl	Mar 30, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Johns Hopkins Genomics, Johns Hopkins University	Aug 20, 2020	Disease-causing CFTR variant. See www.CFTR2.org for phenotype information. -
Pathogenic, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, The Hospital for Sick Children	Jul 23, 2019	- -
Pathogenic, criteria provided, single submitter	curation	Institute of Human Genetics, University of Leipzig Medical Center	Sep 05, 2022	This variant was identified in 2 unrelated patients with a clinically confirmed diagnosis of cystic fibrosis. The variant was classified in the context of a project re-classifying variants in the German Cystic Fibrosis Registry (Muko.e.V.). Link: https://www.muko.info/angebote/qualitaetsmanagement/register/cf-einrichtungen/mukoweb. Criteria applied: PS3_SUP, PM2_SUP, PM3_VSTR, PP3, PP4 -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jul 31, 2023	For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects CFTR function (PMID: 23974870). 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. ClinVar contains an entry for this variant (Variation ID: 53690). This missense change has been observed in individual(s) with cystic fibrosis (PMID: 7517268, 17662673, 23974870, 24225052). This variant is present in population databases (rs139304906, gnomAD 0.0009%). This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 1077 of the CFTR protein (p.Leu1077Pro). -

CFTR-related disorders

Pathogenic:2

Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, The Hospital for Sick Children	Jul 23, 2019	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Mar 17, 2017	- -

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

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

- -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Mayo Clinic Laboratories, Mayo Clinic

Jun 01, 2020

PS3, PM3, PM2, PP3, PP5 -

Bronchiectasis with or without elevated sweat chloride 1

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Oct 07, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.98

BayesDel_addAF

Pathogenic

0.45

BayesDel_noAF

Pathogenic

0.40

Cadd

Pathogenic

Dann

Pathogenic

1.0

DEOGEN2

Uncertain

0.69

D;.;.;D;.

Eigen

Pathogenic

0.88

Eigen_PC

Pathogenic

0.83

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.96

D;D;D;D;D

M_CAP

Pathogenic

0.86

MetaRNN

Pathogenic

0.86

D;D;D;D;D

MetaSVM

Pathogenic

0.87

MutationAssessor

Pathogenic

3.4

M;.;.;.;.

MutationTaster

Benign

1.0

D;D

PrimateAI

Pathogenic

0.88

PROVEAN

Benign

-1.3

N;.;.;N;.

REVEL

Pathogenic

0.83

Sift

Uncertain

0.022

D;.;.;T;.

Sift4G

Pathogenic

0.0

D;.;.;D;.

Polyphen

1.0

D;.;.;.;.

Vest4

0.97

MVP

1.0

MPC

0.012

ClinPred

0.97

GERP RS

5.7

Varity_R

0.98

gMVP

1.0

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