NM_000492.4:c.613C>T

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.613C>T(p.Pro205Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000496 in 1,613,424 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 (★★★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000048 ( 0 hom. )

Consequence

CFTR
NM_000492.4 missense

Scores

Clinical Significance

Pathogenic reviewed by expert panel P:15

Conservation

PhyloP100: 7.52

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 domain ABC transmembrane type-1 1 (size 284) in uniprot entity CFTR_HUMAN there are 65 pathogenic changes around while only 10 benign (87%) in NM_000492.4

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.987

PP5

Variant 7-117535281-C-T is Pathogenic according to our data. Variant chr7-117535281-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 54026.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr7-117535281-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.613C>T	p.Pro205Ser	missense_variant	Exon 6 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.613C>T	p.Pro205Ser	missense_variant	Exon 6 of 27	1	NM_000492.4	ENSP00000003084.6		P13569-1

Frequencies

GnomAD3 genomes

AF:

0.00000660

AC:

AN:

151566

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:

251432

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135886

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000479

AC:

AN:

1461858

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

727222

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000447

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:

0.0000331

GnomAD4 genome

AF:

0.00000660

AC:

AN:

151566

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74030

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

Bravo

AF:

0.00000756

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:15

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Cystic fibrosis

Pathogenic:7

Jan 29, 2018

CFTR-France

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Sep 16, 2015

Counsyl

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 17, 2017

CFTR2

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: research

- -

Aug 29, 2024

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.P205S pathogenic mutation (also known as c.613C>T), located in coding exon 6 of the CFTR gene, results from a C to T substitution at nucleotide position 613. The proline at codon 205 is replaced by serine, an amino acid with similar properties. This mutation was first described in four individuals from two separate families who presented with respiratory symptoms, pancreatic sufficiency, congenital absence of the vas deferens (CBAVD) in one male, and no gastrointestinal features (Chillón M et al. Hum. Mol. Genet., 1993 Oct;2:1741-2). In vitro functional studies revealed that the p.P205S mutant protein had reduced CFTR protein quantity and chloride conductance (Sheppard DN et al. J. Biol. Chem., 1996 Jun;271:14995-5001; Sosnay PR et al. Nat. Genet., 2013 Oct;45:1160-7). This pathogenic mutation is associated with elevated sweat chloride levels and and the majority of individuals are pancreatic sufficient (Sosnay PR et al. Nat. Genet., 2013 Oct;45:1160-7). 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 supporting evidence, this variant is interpreted as a disease-causing mutation. -

Nov 05, 2018

Mendelics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 20, 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.613C>T (p.Pro205Ser) variant involves the alteration of a conserved nucleotide. 5/5 in silico tools predict a damaging outcome for this variant. Pro205 is highly conserved across species and is located in the ABC transporter type 1, transmembrane domain of the cystic fibrosis transmembrane conductance regulator protein. Functional studies have shown that P205S severely impairs chloride conductance, and P205S does not mature and thus does not properly localize to the plasma membrane. This variant was not found in 121408 control chromosomes, but has been cited in both PS- and PI-CF patients reported in the literature. In addition, one reputable database classified this variant as pathogenic. Taken together, this variant is classified as Pathognenic. -

Nov 21, 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 serine, which is neutral and polar, at codon 205 of the CFTR protein (p.Pro205Ser). This variant is present in population databases (rs121908803, gnomAD 0.003%). This missense change has been observed in individuals with cystic fibrosis (PMID: 7505694, 21097845, 25363320). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 54026). 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: 23974870). For these reasons, this variant has been classified as Pathogenic. -

not provided

Pathogenic:3

Feb 27, 2024

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The CFTR c.613C>T (p.Pro205Ser) variant has been reported in the published literature in several individuals affected with cystic fibrosis (CF) and described as pancreatic-sufficient (PMIDs: 16114821(2005), 21097845 (2011), 23857699(2013), 34065744(2021), 34782259 (2021)). Functional studies have shown that this variant caused defects in the maturation and localization of the CFTR protein significantly affecting its function (PMIDs: 8663008 (1996), 9920885 (1999), 23974870 (2013), 34065744 (2021)). The frequency of this variant in the general population, 0.000004 (1/251432 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with pathogenicity. Based on the available information, this variant is classified as pathogenic. -

May 17, 2017

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 26, 2018

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The CFTR c.613C>T; p.Pro205Ser variant (rs121908803) is reported in individuals with cystic fibrosis, commonly associated with the pancreatic sufficient form (CFTR2 database, Chillon 1993, Sheridan 2011, Sosnay 2013). Functional studies of the variant protein show decreased protein maturation and severely impaired chloride channel function (Sheppard 1996). This variant is reported as pathogenic in ClinVar (Variation ID: 54026), and it is found in the general population with a low overall allele frequency of 0.0004% (1/246192 alleles) in the Genome Aggregation Database. The proline at codon 205 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Based on available information, this variant is considered to be moderately pathogenic. REFERENCES CFTR2 database: https://www.cftr2.org Chillon M et al. Identification of a new missense mutation (P205S) in the first transmembrane domain of the CFTR gene associated with a mild cystic fibrosis phenotype. Hum Mol Genet. 1993 Oct;2(10):1741-2. Sheppard DN et al. Contribution of proline residues in the membrane-spanning domains of cystic fibrosis transmembrane conductance regulator to chloride channel function. J Biol Chem. 1996 Jun 21;271(25):14995-5001. Sheridan MB et al. CFTR transcription defects in pancreatic sufficient cystic fibrosis patients with only one mutation in the coding region of CFTR. J Med Genet. 2011 Apr;48(4):235-41. Sosnay PR et al. Defining the disease liability of variants in the cystic fibrosis transmembrane conductance regulator gene. Nat Genet. 2013 Oct;45(10):1160-7. -

CFTR-related disorder

Pathogenic:2

Feb 23, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The CFTR c.613C>T variant is predicted to result in the amino acid substitution p.Pro205Ser. This variant has been reported to be causative for cystic fibrosis (Chillon et al. 1993. PubMed ID: 7505694; Castellani et al. 2008. PubMed ID: 18456578; Sheridan et al. 2011. PubMed ID: 21097845; Sosnay et al. 2013. PubMed ID: 23974870). This variant is reported in 0.0029% of alleles in individuals of Latino descent in gnomAD. This variant is interpreted as pathogenic. -

Mar 17, 2017

Natera, Inc.

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

- -

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 26, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.78

BayesDel_addAF

Pathogenic

0.41

BayesDel_noAF

Pathogenic

0.44

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.90

D;.;.;D;.

Eigen

Pathogenic

0.75

Eigen_PC

Uncertain

0.65

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.97

D;D;D;D;D

M_CAP

Pathogenic

0.58

MetaRNN

Pathogenic

0.99

D;D;D;D;D

MetaSVM

Pathogenic

0.92

MutationAssessor

Pathogenic

3.0

M;.;.;.;M

PrimateAI

Uncertain

0.63

PROVEAN

Pathogenic

-6.5

D;.;.;D;.

REVEL

Pathogenic

0.87

Sift

Pathogenic

0.0

D;.;.;D;.

Sift4G

Pathogenic

0.0

D;.;.;D;.

Polyphen

1.0

D;.;.;.;.

Vest4

0.98

MutPred

0.88

Loss of stability (P = 0.2069);Loss of stability (P = 0.2069);Loss of stability (P = 0.2069);.;Loss of stability (P = 0.2069);

MVP

1.0

MPC

0.017

ClinPred

1.0

GERP RS

5.5

Varity_R

0.93

gMVP

0.94

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