7-117530957-C-T

Position:

chr7-117530957-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1PM2PM5PP3_ModeratePP5

The NM_000492.4(CFTR):c.332C>T(p.Pro111Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00015 in 1,613,652 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P111A) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.000085 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00016 ( 0 hom. )

Consequence

CFTR
NM_000492.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:11

Conservation

PhyloP100: 4.62

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 Likely_pathogenic. Variant got 9 ACMG points.

PM1

In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 14 uncertain in NM_000492.4

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr7-117530956-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 53718.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=1, not_provided=1, Likely_pathogenic=1, Uncertain_significance=1}.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.904

PP5

Variant 7-117530957-C-T is Pathogenic according to our data. Variant chr7-117530957-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 53720.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=10, Pathogenic=1, Likely_pathogenic=1}. Variant chr7-117530957-C-T 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.332C>T	p.Pro111Leu	missense_variant	4/27	ENST00000003084.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CFTR	ENST00000003084.11 linkuse as main transcript	c.332C>T	p.Pro111Leu	missense_variant	4/27	1	NM_000492.4	P2	P13569-1

Frequencies

GnomAD3 genomes

AF:

0.0000854

AC:

AN:

152166

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

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:

0.000176

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000597

AC:

AN:

251086

Hom.:

AF XY:

0.0000663

AC XY:

AN XY:

135670

show subpopulations

Gnomad AFR exome

AF:

0.0000616

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:

0.0000462

Gnomad NFE exome

AF:

0.000106

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000157

AC:

229

AN:

1461486

Hom.:

Cov.:

AF XY:

0.000154

AC XY:

112

AN XY:

727024

show subpopulations

Gnomad4 AFR exome

AF:

0.0000598

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:

0.0000187

Gnomad4 NFE exome

AF:

0.000199

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000854

AC:

AN:

152166

Hom.:

Cov.:

AF XY:

0.0000942

AC XY:

AN XY:

74332

show subpopulations

Gnomad4 AFR

AF:

0.0000241

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:

0.000176

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000141

Hom.:

Bravo

AF:

0.0000831

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ExAC

AF:

0.0000659

AC:

EpiCase

AF:

0.000218

EpiControl

AF:

0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2Uncertain:11

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:5

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Dec 16, 2022	Identified as being possibly associated with CFTR-related disorders, however, functional studies show that this variant only slightly reduced mutant protein biosynthesis, stability, and chloride efflux ability compared to wild type (Hammerle et al., 2001), and several reports of P111L in the published literature describe individuals with non-obstructive azoospermia and chronic bronchitis who were not found to harbor a second CFTR variant in trans (Bombieri et al., 1998; Larriba et al., 2005); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 21520337, 10200050, 26990548, 11278813, 26277102, 29484681, 24727426, 24451227, 9921909, 28603918, 34996830, 33572515, 16128988) -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Aug 22, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jan 30, 2023	The frequency of this variant in the general population, 0.00011 (14/128988 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant occurs with a second, pathogenic CFTR variant in an individual with congenital bilateral absence of vas deferens (CBVAD) (PMIDs: 21520337 (2011), 10200050 (1998)). Additionally, the variant is reported in individuals with cystic fibrosis (CF) (PMIDs: 34782259 (2021), 26990548 (2016)), chronic bronchitis (PMID: 9921909 (1998)), non-obstructive azoospermia (PMID: 16128988 (2005)), and in healthy individuals (PMID: 24451227 (2014)). Functional studies report the variant slightly destabilizes gene function (PMID: 11278813 (2001)), however further studies are needed. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant. -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Dec 02, 2022	The CFTR c.332C>T; p.Pro111Leu variant (rs140502196) is described in the literature in individuals with atypical cystic fibrosis (i.e. congenital bilateral absence of the vas deferens (CBAVD), isolated pulmonary disease) (Bombieri 1998, de Meeus 1998, Larriba 2005). One affected individual carried a second pathogenic variant in CFTR (de Meeus 1998); however, additional pathogenic variants were not identified in other affected individuals (Bombieri 1998, Larriba 2005). The p.Pro111Leu variant is also reported in ClinVar (Variation ID: 53720). This variant is found in the general population with a low overall allele frequency of 0.006% (17/282480 alleles) in the Genome Aggregation Database. The proline at codon 111 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.842). While functional studies indicate wildtype chloride channel activity at room temperature, this variant exhibits a defect in gating potential at physiological temperatures, suggesting altered activity under conditions closer to those in human tissues (Hammerle 2001). Another variant at the same codon (p.Pro111Ala) exhibits altered gating kinetics (Hammerle 2001) and is reported in an individual with CBAVD who carried a pathogenic variant on the opposite allele (SickKids CFTR database). Although the p.Pro111Leu variant is unlikely to be causative for classic cystic fibrosis, based on available information, we consider it uncertain whether it is pathogenic for other CFTR-related disorders. References: Link to SickKids CFTR database: http://www.genet.sickkids.on.ca/cftr/Home.html Bombieri C et al. Complete mutational screening of the CFTR gene in 120 patients with pulmonary disease. Hum Genet. 1998 Dec;103(6):718-22. PMID: 9921909 de Meeus A et al. Genetic findings in congenital bilateral aplasia of vas deferens patients and identification of six novel mutatations. Mutations in brief no. 138. Online. Hum Mutat. 1998;11(6):480. PMID: 10200050. Hammerle MM et al. Disease-associated mutations in the extracytoplasmic loops of cystic fibrosis transmembrane conductance regulator do not impede biosynthetic processing but impair chloride channel stability. J Biol Chem. 2001 May 4;276(18):14848-54. PMID: 11278813 Larriba S et al. Molecular evaluation of CFTR sequence variants in male infertility of testicular origin. Int J Androl. 2005 Oct;28(5):284-90. PMID: 16128988 -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 21, 2017	- -

Cystic fibrosis

Pathogenic:1Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 22, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Nov 04, 2022	This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 111 of the CFTR protein (p.Pro111Leu). This variant is present in population databases (rs140502196, gnomAD 0.01%). This missense change has been observed in individual(s) with congenital bilateral aplasia of the vas deferens (PMID: 10200050). ClinVar contains an entry for this variant (Variation ID: 53720). 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. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on CFTR function (PMID: 11278813). 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Dec 27, 2022	The p.P111L variant (also known as c.332C>T), located in coding exon 4 of the CFTR gene, results from a C to T substitution at nucleotide position 332. The proline at codon 111 is replaced by leucine, an amino acid with similar properties. This alteration has been reported with another mutation in association with congenital bilateral absence of vas deferens (de Meeus A et al. Hum. Mutat., 1998;11:480; Steiner B et al. Hum Mutat, 2011 Aug;32:912-20), in the heterozygous state in an individual with chronic bronchitis (Bombieri C et al. Hum. Genet., 1998 Dec;103:718-22), and in the heterozygous state in an individual with non-obstructive azoospermia (Larriba S et al. Int. J. Androl., 2005 Oct;28:284-90). In vitro studies suggested a difference in channel activity between the mutant and wild type under a specific temperature condition (Hämmerle MM et al. J. Biol. Chem., 2001 May;276:14848-54). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on available evidence to date, the clinical significance of this alteration remains unclear. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Johns Hopkins Genomics, Johns Hopkins University	Dec 01, 2023	This CFTR missense variant has been identified in individuals with features of cystic fibrosis, but not a classic cystic fibrosis phenotype. It (rs140502196) is rare (<0.1%) in a large population dataset (gnomADv4.0.0: 242/1613652 total alleles; 0.015%; no homozygotes) and has an entry in ClinVar (Variation ID: 53720). The proline residue at this position is highly evolutionarily conserved across the species assessed. A single published functional study demonstrates that p.Pro111Leu may have a subtle impact on CFTR protein function and this is supported by an unpublished study that indicates that this variant decreases the conductance of CFTR to a level that is consistent with that of a variant associated with varying clinical consequence. We consider CFTR c.332C>T to be a likely pathogenic variant associated with varying clinical consequence. -

CFTR-related disorder

Pathogenic:1Uncertain:1

Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Nov 25, 2020	- -
Pathogenic, criteria provided, single submitter	curation	CFTR-France	Jan 24, 2024	- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Mar 05, 2024

Variant summary: CFTR c.332C>T (p.Pro111Leu) results in a non-conservative amino acid change located in the ABC transporter type 1, transmembrane domain (IPR011527) 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 6.3e-05 in 252330 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in CFTR causing Congenital Bilateral Absence Of The Vas Deferens/Cystic Fibrosis, allowing no conclusion about variant significance. c.332C>T has been reported in the literature with c.3909C>G(p.Asn1303Lys) in at least one individual affected with Congenital Bilateral Absence Of The Vas Deferens (e.g. deMeeus_1998) and as an uninformative genotype (i.e. zygosity not specified) in a cohort of individuals with positive CF newborn screening results (Bozdogan_2021). These data do not allow any conclusion about variant significance. At least one publication reports experimental evidence evaluating an impact on protein function. These results showed no damaging effect of this variant (Hammerle_2001). The following publications have been ascertained in the context of this evaluation (PMID: 9921909, 16128988, 21520337, 11278813, 10200050, 24451227, 24727426, 33572515). ClinVar contains an entry for this variant (Variation ID: 53720). Based on the evidence outlined above, the variant was classified as uncertain significance. -

See cases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Apr 14, 2021

ACMG classification criteria: PM2, PM3, PP3 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Pathogenic

0.32

BayesDel_noAF

Pathogenic

0.44

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.76

.;D;.;.;T;.

Eigen

Uncertain

0.62

Eigen_PC

Uncertain

0.62

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.96

D;D;D;D;D;D

M_CAP

Pathogenic

0.90

MetaRNN

Pathogenic

0.90

D;D;D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Uncertain

2.4

.;M;.;.;.;M

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.67

PROVEAN

Pathogenic

-9.1

D;D;.;.;D;.

REVEL

Pathogenic

0.84

Sift

Uncertain

0.0020

D;T;.;.;T;.

Sift4G

Uncertain

0.015

D;D;.;.;D;.

Polyphen

1.0

.;D;.;.;.;.

Vest4

0.89

MVP

1.0

MPC

0.0051

ClinPred

0.96

GERP RS

5.7

Varity_R

0.44

gMVP

0.92

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