rs193922501

Positions:

chr7-117480108-C-T

Variant summary

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

The NM_000492.4(CFTR):c.14C>T(p.Pro5Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000217 in 1,613,770 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 Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000021 ( 0 hom. )

Consequence

CFTR
NM_000492.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:17

Conservation

PhyloP100: 3.85

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:

CFTR (HGNC:):

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 topological_domain Cytoplasmic (size 76) in uniprot entity CFTR_HUMAN there are 14 pathogenic changes around while only 2 benign (88%) in NM_000492.4

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.922

PP5

Variant 7-117480108-C-T is Pathogenic according to our data. Variant chr7-117480108-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 35824.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-117480108-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CFTR	NM_000492.4 linkuse as main transcript	c.14C>T	p.Pro5Leu	missense_variant	1/27	ENST00000003084.11	NP_000483.3	P13569-1A0A024R730

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CFTR	ENST00000003084.11 linkuse as main transcript	c.14C>T	p.Pro5Leu	missense_variant	1/27	1	NM_000492.4	ENSP00000003084.6		P13569-1

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152052

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:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000239

AC:

AN:

251160

Hom.:

AF XY:

0.0000442

AC XY:

AN XY:

135748

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:

0.0000529

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000212

AC:

AN:

1461718

Hom.:

Cov.:

AF XY:

0.0000303

AC XY:

AN XY:

727166

show subpopulations

Gnomad4 AFR exome

AF:

0.00

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:

0.0000234

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152052

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74260

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:

0.0000588

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000557

Hom.:

Bravo

AF:

0.0000264

ExAC

AF:

0.0000247

AC:

EpiCase

AF:

0.000164

EpiControl

AF:

0.000178

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:17

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Cystic fibrosis

Pathogenic:7

Likely pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Jan 09, 2024	The p.P5L variant (also known as c.14C>T), located in coding exon 1 of the CFTR gene, results from a C to T substitution at nucleotide position 14. The proline at codon 5 is replaced by leucine, an amino acid with similar properties. This alteration has been detected in multiple individuals carrying a second CFTR alteration (six with p.F508del, two with p.W1282*, and one with p.R347P) with varying disease severity. The majority of individuals had pancreatic sufficiency, mild or no respiratory symptoms, normal lung function, and elevated sweat chloride levels (Spicuzza L et al. J. Cyst. Fibros., 2012 Jan;11:30-3; Sofia VM et al. Mol. Med., 2018 07;24:38). This variant has also been identified in multiple newborns with abnormal newborn screening results (Narzi L et al. Clin. Genet., 2007 Jul;72:39-46; Paracchini V et al. JIMD Rep, 2012 Nov;4:17-23), as well as in an individual with idiopathic chronic pancreatitis (Steiner B et al. Hum. Mutat., 2011 Aug;32:912-20). In two functional studies, this variant demonstrated a reduced level of WT-CFTR protein function; in addition, the protein was predominantly localized intracellularly and demonstrated abnormal channel gating activity (Gené GG et al. Hum. Mutat., 2008 May;29:738-49; Raraigh KS et al. Am. J. Hum. Genet., 2018 06;102:1062-1077). The p.P5L alteration has been reported as a variant of varying clinical consequences (VVCC) (Sosnay PR et al. Pediatr. Clin. North Am., 2016 08;63:585-98; The Clinical and Functional TRanslation of CFTR (CFTR2); available at http://cftr2.org. Accessed January 22, 2018). 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 the majority of available evidence to date, this variant is likely to be pathogenic. -
Likely pathogenic, criteria provided, single submitter	literature only	Counsyl	Mar 13, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	Mar 30, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 17, 2024	Variant summary: CFTR c.14C>T (p.Pro5Leu) results in a non-conservative amino acid change in 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 2.4e-05 in 251348 control chromosomes. c.14C>T has been reported in the literature in multiple individuals affected with Non-classic Cystic Fibrosis, ICP, and CF (e.g. Chirico_2014, Narzi_2007, Sanz_2010, Schneider_2007, Spicuzza_2011). Multiple authors have indicated that the variant could cause a mild form of CF. These data indicate that the variant is very likely to be associated with disease. Co-occurrence with a pathogenic variant, CFTR 5T_TG11, has been reported (Narzi_2007). At least one publication reports experimental evidence evaluating an impact on protein function, with the most pronounced variant effect resulting in 10%-30% of normal activity (Thelin_2007, Gene_2008, Raraigh_2018). The following publications have been ascertained in the context of this evaluation (PMID: 17331079, 9439669, 19897426, 15758663, 18306312, 17594398, 20351098, 19724303, 17594397, 20351101, 17235394, 21983161, 19318035, 11938439, 25735457, 27264265, 25658530, 28736296, 29805046, 33374015). ClinVar contains an entry for this variant (Variation ID: 35824). Based on the evidence outlined above, the variant was classified as pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 22, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 13, 2024	This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 5 of the CFTR protein (p.Pro5Leu). This variant is present in population databases (rs193922501, gnomAD 0.006%). This missense change has been observed in individuals with bronchiectasis, chronic pancreatitis, cystic fibrosis, and/or other CFTR-related disorders (PMID: 18306312, 19724303, 21520337, 21983161, 25910067). ClinVar contains an entry for this variant (Variation ID: 35824). 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 95%. Experimental studies have shown that this missense change affects CFTR function (PMID: 17235394, 18306312, 29805046, 30046002). For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Apr 04, 2024	- -

not provided

Pathogenic:5

Likely pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 20, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 04, 2023	The CFTR c.14C>T; p.Pro5Leu variant (rs193922501) is described as a variant of varying clinical consequences (CFTR2 database). It has been observed in trans with a pathogenic severe variant (i.e. F508del) in individuals who were either asymptomatic, had atypical/mild cystic fibrosis, or were diagnosed with pancreatic sufficient or insufficient cystic fibrosis (CFTR2 database, Casals 1997, Gene 2008, Narzi 2007, Schneider 2007, Spicuzza 2012). Functional characterization of the variant indicates a failure to generate mature CFTR protein and localization to the plasma membrane, and has 10-25% function as wild type protein (Gene 2008, Raraigh 2018, Thelin 2007). This variant is reported in ClinVar (Variation ID: 35824). It is found in the general population with a low overall allele frequency of 0.002% (7/282536 alleles) in the Genome Aggregation Database. The proline at codon 5 is well conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Based on available information, this variant is classified as pathogenic with varying clinical consequences. REFERENCES CFTR2: https://www.cftr2.org/ Casals T et al. High heterogeneity for cystic fibrosis in Spanish families: 75 mutations account for 90% of chromosomes. Hum Genet. 1997 Dec;101(3):365-70. Gene GG et al. N-terminal CFTR missense variants severely affect the behavior of the CFTR chloride channel. Hum Mutat. 2008 May;29(5):738-49. Narzi L et al. Does cystic fibrosis neonatal screening detect atypical CF forms? Extended genetic characterization and 4-year clinical follow-up. Clin Genet. 2007 Jul;72(1):39-46. Schneider M et al. Large deletions in the CFTR gene: clinics and genetics in Swiss patients with CF. Clin Genet. 2007 Jul;72(1):30-8. 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. Spicuzza L et al. Mild cystic fibrosis in patients with the rare P5L CFTR mutation. J Cyst Fibros. 2012 Jan;11(1):30-3. Thelin WR et al. Direct interaction with filamins modulates the stability and plasma membrane expression of CFTR. J Clin Invest. 2007 Feb;117(2):364-74. -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 01, 2022	Published functional studies demonstrate a damaging effect on chloride channel activity, protein maturation, and cellular localization (Thelin 2007, Gene 2008, Han 2018, Raraigh 2018); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Classified as a variant of varying clinical consequence in a well-curated database (CFTR2); This variant is associated with the following publications: (PMID: 31036917, 34426522, 29805046, 31328366, 20351101, 20351098, 17235394, 9439669, 25735457, 18306312, 23430892, 25910067, 30134826, 28736296, 27264265, 19897426, 19318035, 17594398, 17331079, 17137500, 33572515, 30046002, 25754095, 25658530, 31776420, 15758663, 21520337, 11938439, 17594397, 19724303, 21983161) -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2022	CFTR: PM3:Very Strong, PM2, PS3:Supporting -
Likely pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jun 26, 2024	The CFTR c.14C>T (p.Pro5Leu) variant is associated with a variable phenotype (see CFTR2 (http://cftr2.org/)). In the published literature, this variant has been reported in individuals with cystic fibrosis (PMIDs: 25658530 (2015), 25754095 (2015), 21983161 (2012), 19724303 (2010), 17331079 (2007), 17137500 (2006), 9439669 (1997)), atypical/mild CF symptoms (PMIDs: 31328366 (2019), 21983161 (2012), 19318035 (2009), 17594397 (2007)), and CFTR-related disorders (PMIDs: 34996830 (2022), 33374015 (2020), 27264265 (2016), 21520337 (2011), 15758663 (2005), 11938439 (2002)). Functional studies indicate this variant has deleterious effects on CFTR protein expression and ion channel activity (PMIDs: 29805046 (2018), 18306312 (2008), 17235394 (2007)). The frequency of this variant in the general population, 0.000054 (7/128930 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Based on the available information, this variant is classified as likely pathogenic. -

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

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

- -

CFTR-related disorder

Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 03, 2024

The CFTR c.14C>T variant is predicted to result in the amino acid substitution p.Pro5Leu. This variant has been reported in the compound heterozygous state in individuals with cystic fibrosis or chronic pancreatitis, typically with mild features and a second pathogenic variant that has been associated with severe forms of cystic fibrosis such as p.Phe508del (Gené et al. 2008. PubMed ID: 18306312; Thelin et al. 2007. PubMed ID: 17235394; Spicuzza et al. 2012. PubMed ID: 21983161; Steiner et al. 2011. PubMed ID: 21520337). In vitro studies indicate this variant results in impaired CFTR function, presumably through a loss of glycosylation leading to intracellular retention of the receptor (Gené et al. 2008. PubMed ID: 18306312). However, to our knowledge there are no reports of individuals with classic cystic fibrosis who are homozygous for this variant. This variant is reported in 0.0054% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as likely pathogenic. -

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

Likely pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Apr 05, 2024

- -

Bronchiectasis with or without elevated sweat chloride 1

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Mar 27, 2024

- -

Cystic fibrosis;C5924204:CFTR-related disorder

Pathogenic:1

Pathogenic, criteria provided, single submitter

curation

CFTR-France

Aug 04, 2020

when the variant is in trans with another CF-causing variation, can either result in CF or in a CFTR-RD -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.75

BayesDel_addAF

Pathogenic

0.26

BayesDel_noAF

Pathogenic

0.29

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.87

D;.;.;T;.

Eigen

Pathogenic

0.70

Eigen_PC

Uncertain

0.61

FATHMM_MKL

Uncertain

0.84

LIST_S2

Uncertain

0.92

D;D;D;D;D

M_CAP

Pathogenic

0.63

MetaRNN

Pathogenic

0.92

D;D;D;D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Pathogenic

3.3

M;.;.;.;M

PrimateAI

Uncertain

0.65

PROVEAN

Pathogenic

-6.3

D;.;.;D;.

REVEL

Pathogenic

0.89

Sift

Pathogenic

0.0

D;.;.;D;.

Sift4G

Pathogenic

0.0

D;.;.;D;.

Polyphen

1.0

D;.;.;.;.

Vest4

0.69

MutPred

0.73

Loss of glycosylation at P5 (P = 0.0149);Loss of glycosylation at P5 (P = 0.0149);Loss of glycosylation at P5 (P = 0.0149);Loss of glycosylation at P5 (P = 0.0149);Loss of glycosylation at P5 (P = 0.0149);

MVP

0.99

MPC

0.011

ClinPred

0.92

GERP RS

4.2

Varity_R

0.86

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