rs368505753

Positions:

chr7-117509069-C-T

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/exons	MANE	Protein	UniProt
CFTR	NM_000492.4 linkuse as main transcript	c.200C>T	p.Pro67Leu	missense_variant	3/27	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.200C>T	p.Pro67Leu	missense_variant	3/27	1	NM_000492.4	ENSP00000003084	P2	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:9

Pathogenic, criteria provided, single submitter	curation	CFTR-France	Jan 29, 2018	- -
Pathogenic, reviewed by expert panel	research	CFTR2	Mar 17, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	May 27, 2020	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Johns Hopkins Genomics, Johns Hopkins University	Oct 16, 2019	Disease-causing CFTR variant (previously reported for this patient by mass spectrometry genotyping). See www.CFTR2.org for phenotype information. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 29, 2016	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Jul 26, 2021	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. -
Likely pathogenic, criteria provided, single submitter	literature only	Counsyl	Sep 24, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 05, 2024	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). 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 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, The Hospital for Sick Children	Jul 05, 2021	- -

not provided

Pathogenic:8

Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jun 08, 2022	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 09, 2018	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	Feb 02, 2021	PS3, PP2, PM3_Supporting, PM2 -
Likely pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 02, 2023	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Aug 22, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Feb 24, 2023	PS3, PM2, PM3_strong, PP3, PP4, PP5 -

CFTR-related disorder

Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	-	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. -
Pathogenic, no assertion criteria provided	clinical testing	PreventionGenetics, part of Exact Sciences	Jan 01, 2024	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. -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Mar 17, 2017	- -
Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, The Hospital for Sick Children	Jul 05, 2021	- -

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

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

- -

Hereditary pancreatitis

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Mendelics

May 04, 2022

- -

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

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Dec 14, 2021

- -

Bronchiectasis with or without elevated sweat chloride 1

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Mar 28, 2024

- -

ivacaftor response - Efficacy

Other:1

drug response, reviewed by expert panel

curation

PharmGKB

Mar 24, 2021

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

MutationTaster

Benign

1.0

D;D

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