rs368505753

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PP3_StrongPP5_Very_Strong

The NM_000492.4(CFTR):c.200C>T(p.Pro67Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000109 in 1,612,926 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,drug response (★★★).

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00012 ( 0 hom. )

Consequence

CFTR
NM_000492.4 missense

Scores

Clinical Significance

Pathogenic; drug response reviewed by expert panel P:25O:1

Conservation

PhyloP100: 6.12

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 16 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, 0.974

PP5

Variant 7-117509069-C-T is Pathogenic according to our data. Variant chr7-117509069-C-T is described in ClinVar as [Pathogenic, drug_response]. Clinvar id is 53425.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr7-117509069-C-T is described in Lovd as [Pathogenic]. Variant chr7-117509069-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CFTR	NM_000492.4 link	c.200C>T	p.Pro67Leu	missense_variant	Exon 3 of 27	ENST00000003084.11	NP_000483.3	P13569-1A0A024R730

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CFTR	ENST00000003084.11 link	c.200C>T	p.Pro67Leu	missense_variant	Exon 3 of 27	1	NM_000492.4	ENSP00000003084.6		P13569-1

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

152202

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000482

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:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000359

AC:

AN:

251004

Hom.:

AF XY:

0.0000442

AC XY:

AN XY:

135656

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:

0.0000793

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000117

AC:

171

AN:

1460724

Hom.:

Cov.:

AF XY:

0.000114

AC XY:

AN XY:

726752

show subpopulations

Gnomad4 AFR exome

AF:

0.0000897

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:

0.000143

Gnomad4 OTH exome

AF:

0.000149

GnomAD4 genome

AF:

0.0000329

AC:

AN:

152202

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74348

show subpopulations

Gnomad4 AFR

AF:

0.0000482

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:

0.0000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000855

Hom.:

Bravo

AF:

0.0000491

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000330

AC:

EpiCase

AF:

0.000164

EpiControl

AF:

0.000119

ClinVar

Significance: Pathogenic; drug response

Submissions summary: Pathogenic:25Other:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Cystic fibrosis

Pathogenic:10

Jul 05, 2021

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 24, 2014

Counsyl

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: literature only

- -

Oct 16, 2019

Johns Hopkins Genomics, Johns Hopkins University

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Disease-causing CFTR variant (previously reported for this patient by mass spectrometry genotyping). See www.CFTR2.org for phenotype information. -

Mar 17, 2017

CFTR2

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: research

- -

Dec 03, 2024

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.P67L pathogenic mutation (also known as c.200C>T), located in coding exon 3 of the CFTR gene, results from a C to T substitution at nucleotide position 200. The proline at codon 67 is replaced by leucine, an amino acid with similar properties. This mutation has been described in a Scottish cohort of individuals with a mild phenotype, including in trans with p.G542* in an 18-year-old male with recurrent chest infections and pancreatic insufficiency as well as in trans with p.F508del in a 1-year-old female with a probable diagnosis of cystic fibrosis (CF) and an initial abnormal sweat chloride level followed by two equivocal sweat chloride tests (Gilfillan A et al. J. Med. Genet., 1998 Feb;35:122-5). In vitro functional studies showed that while CFTR transcripts with this pathogenic mutation had similar mRNA levels compared to wildtype, the amount of processed mature protein was significantly decreased (Van Goor F et al. J. Cyst. Fibros., 2014 Jan;13:29-36). This mutation is associated with borderline sweat chloride levels and pancreatic sufficiency (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. -

Dec 03, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 67 of the CFTR protein (p.Pro67Leu). This variant is present in population databases (rs368505753, gnomAD 0.006%). This missense change has been observed in individual(s) with cystic fibrosis (CF), congenital bilateral absence of vas deferens, or other CFTR-related conditions (PMID: 9507391, 16840743, 22658665, 23974870). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 53425). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt CFTR protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects CFTR function (PMID: 23891399, 23974870). For these reasons, this variant has been classified as Pathogenic. -

Jan 29, 2018

CFTR-France

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Jul 29, 2016

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: The CFTR c.200C>T (p.Pro67Leu) variant involves the alteration of a conserved nucleotide and is present in ABC transporter type 1, transmembrane domain of the protein. 5/5 in silico tools predict a damaging outcome for this variant. This variant was found in 4/121266 control chromosomes at a frequency of 0.000033, which does not exceed the estimated maximal expected allele frequency of a pathogenic CFTR variant (0.0129603). The variant has been reported in numerous CF-affected individuals in the literature, particularly in patients with non-classic CF with consistent recessive genotypes, and has been shown to display a mean chloride conductance <10% compared to wildtype (Sosnay_2013, Kraus_2007). In addition, multiple clinical diagnostic laboratories/reputable databases have classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. -

Sep 16, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The CFTR c.200C>T; p.Pro67Leu variant (rs368505753), is reported in the literature in multiple individuals in the compound heterozygous state affected with cystic fibrosis (Gilfillan 1998, Kingsmore 2021, Raraigh 2022, Sosnay 2013). This variant is reported in ClinVar (Variation ID: 53425) and is observed on ten alleles in the Genome Aggregation Database, indicating it is not a common polymorphism and. In vitro/In vivo functional analyses demonstrate altered CFTR protein folding, reduced mature CTFR protein, and reduced chloride transport (Sabusap 2021, Van Goor 2014). The proline at codon 67 is highly conserved and computational analyses predict that this variant is deleterious (REVEL:0.926). Based on available information, this variant is considered to be pathogenic. References: Gilfillan A, et al. P67L: a cystic fibrosis allele with mild effects found at high frequency in the Scottish population. J Med Genet. 1998. PMID: 9507391 Kingsmore SF, et al. A genome sequencing system for universal newborn screening, diagnosis, and precision medicine for severe genetic diseases. 2021. Am J Hum Genet. PMID: 36007526. Raraigh KS, et al. Complete CFTR gene sequencing in 5,058 individuals with cystic fibrosis informs variant-specific treatment. J Cyst Fibros. 2022. PMID: 34782259. Sabusap CM, et al. The CFTR P67L variant reveals a key role for N-terminal lasso helices in channel folding, maturation, and pharmacologic rescue. 2021. J Biol Chem. PMID: 33781744. Sosnay PR, et al. Defining the disease liability of variants in the cystic fibrosis transmembrane conductance regulator gene. Nat Genet. 2013. PMID: 23974870. Van Goor F, et al. Effect of ivacaftor on CFTR forms with missense mutations associated with defects in protein processing or function. J Cyst Fibros. 2014. PMID: 23891399. -

May 27, 2020

Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has been previously reported as a compound heterozygous change in many individuals affected with cystic fibrosis (CF), congenital bilateral absence of vas deferens, or other CFTR-related conditions (PMID: 9507391, 22658665, 23974870, 16840743). Individuals with this variant and a second pathogenic allele are typically found to have lower sweat chloride levels than the average CF (http://cftr2.org/mutation/scientific/P67L/). Experimental studies have shown that this missense change affects the chloride conduction function in vitro (PMID:23974870, 23891399). It is present in the heterozygous state in the gnomAD population database at a frequency of 0.004% (10/282408) and thus is presumed to be rare. In silico analyses support a deleterious effect of the c.200C>T (p.Pro67Leu) variant on protein function. Based on the available evidence, the c.200C>T (p.Pro67Leu) variant is classified as Pathogenic. -

not provided

Pathogenic:7

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jun 08, 2022

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In the published literature, the variant has been associated with mild CF signs and symptoms with compound heterozygous individuals often being pancreatic sufficient, have abnormal sweat chloride levels, and are responsive to therapeutics (PMID: 6840743 (1983), 23974870 (2013), 25732475 (2015), 28392015 (2017)). The variant has been reported to be common in the Scottish population (PMID: 9507391 (1998)). Functional studies have shown that this variant has a damaging effect on CFTR maturation and function (PMID: 23974870 (2013), 23891399 (2014), 27660821 (2016), 33781744 (2021)). Based on the available information, this variant is classified as pathogenic. -

Feb 02, 2021

Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PS3, PP2, PM3_Supporting, PM2 -

Jul 26, 2024

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 09, 2018

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Aug 22, 2022

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

CFTR-related disorder

Pathogenic:4

Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has been previously reported as a compound heterozygous change in multiple individuals with cystic fibrosis (CF) and other CFTR-related disorders (PMID: 9507391, 22658665, 23974870, 16840743). The c.200C>T (p.Pro67Leu) variant is present in the CFTR2 website as a CF disease-causing variant when combined with another CF-causing variant (http://cftr2.org/mutation/scientific/P67L/). In-vitro functional studies showed that this alteration affects the channel function (PMID:23974870, 23891399). It is present in the heterozygous state in the gnomAD population database at a frequency of 0.004% (10/282408) and thus is presumed to be rare. In silico analyses support a deleterious effect of the c.200C>T (p.Pro67Leu) variant on protein function. Based on the available evidence, the c.200C>T (p.Pro67Leu) variant is classified as Pathogenic. -

Jan 01, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The CFTR c.200C>T variant is predicted to result in the amino acid substitution p.Pro67Leu. This variant has been reported to be causative for cystic fibrosis (https://cftr2.org, Sosnay et al. 2013. PubMed ID: 23974870; Claustres et al. 1993. PubMed ID: 7691344). In summary, we classify this variant as pathogenic. -

Mar 17, 2017

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jul 05, 2021

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

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

Pathogenic:1

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary pancreatitis

Pathogenic:1

May 04, 2022

Mendelics

Significance: 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

May 23, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Bronchiectasis with or without elevated sweat chloride 1

Pathogenic:1

Mar 28, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

ivacaftor response - Efficacy

Other:1

Mar 24, 2021

PharmGKB

Significance: drug response

Review Status: reviewed by expert panel

Collection Method: curation

PharmGKB Level of Evidence 1A: Level 1A clinical annotations describe variant-drug combinations that have variant-specific prescribing guidance available in a current clinical guideline annotation or an FDA-approved drug label annotation. Annotations of drug labels or clinical guidelines must give prescribing guidance for specific variants (e.g. CYP2C9*3, HLA-B*57:01) or provide mapping from defined allele functions to diplotypes and phenotypes to be used as supporting evidence for a level 1A clinical annotation. Level 1A clinical annotations must also be supported by at least one publication in addition to a clinical guideline or drug label with variant-specific prescribing guidance. Drug-variant association: Efficacy

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.65

BayesDel_addAF

Pathogenic

0.35

BayesDel_noAF

Pathogenic

0.45

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.88

D;.;.;T;.

Eigen

Pathogenic

0.98

Eigen_PC

Pathogenic

0.91

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.96

D;D;D;D;D

M_CAP

Pathogenic

0.58

MetaRNN

Pathogenic

0.97

D;D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

4.0

H;.;.;.;H

PrimateAI

Uncertain

0.58

PROVEAN

Pathogenic

-7.1

D;.;.;D;.

REVEL

Pathogenic

0.93

Sift

Pathogenic

0.0

D;.;.;D;.

Sift4G

Pathogenic

0.0

D;.;.;D;.

Polyphen

1.0

D;.;.;.;.

Vest4

0.94

MVP

0.99

MPC

0.017

ClinPred

0.99

GERP RS

5.7

Varity_R

0.84

gMVP

0.93

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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