NM_000492.4(CFTR):c.613C>T (p.Pro205Ser) AND Cystic fibrosis

Germline classification:: Pathogenic (7 submissions)
Last evaluated:: Mar 17, 2017
Review status:: 3 stars out of maximum of 4 stars
reviewed by expert panel

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000056400.17

Allele description [Variation Report for NM_000492.4(CFTR):c.613C>T (p.Pro205Ser)]

NM_000492.4(CFTR):c.613C>T (p.Pro205Ser)

Gene:

CFTR:CF transmembrane conductance regulator [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

7q31.2

Genomic location:

Preferred name:

NM_000492.4(CFTR):c.613C>T (p.Pro205Ser)

HGVS:

NC_000007.14:g.117535281C>T
NG_016465.4:g.74498C>T
NM_000492.4:c.613C>TMANE SELECT
NP_000483.3:p.Pro205Ser
NP_000483.3:p.Pro205Ser
LRG_663t1:c.613C>T
LRG_663:g.74498C>T
LRG_663p1:p.Pro205Ser
NC_000007.13:g.117175335C>T
NM_000492.3:c.613C>T
P13569:p.Pro205Ser

Protein change:

P205S

Links:

UniProtKB: P13569#VAR_000135; dbSNP: rs121908803

NCBI 1000 Genomes Browser:

rs121908803

Molecular consequence:

NM_000492.4:c.613C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Cystic fibrosis (CF)
Synonyms:: Mucoviscidosis
Identifiers:: MONDO: MONDO:0009061; MedGen: C0010674; Orphanet: 586; OMIM: 219700

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000071514	CFTR2 - CFTR2	reviewed by expert panel (Sosnay PR et al. (Nat Genet 2013))	Pathogenic (Mar 17, 2017)	germline	research	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV000697038	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Jul 20, 2016)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 8663008, 21097845, 9920885, 23974870 LabCorp Variant Classification Summary - May 2015.docx, Citation Link,
SCV000886189	Mendelics	criteria provided, single submitter (Mendelics Assertion Criteria 2017)	Pathogenic (Nov 5, 2018)	unknown	clinical testing	Citation Link,
SCV001132149	Counsyl	no assertion criteria provided	Likely pathogenic (Sep 16, 2015)	unknown	clinical testing	PubMed (4) [See all records that cite these PMIDs] 8663008, 23974870, 11938353, 10225950
SCV001169322	CFTR-France	criteria provided, single submitter (Claustres M et al. (Hum Mutat 2017))	Pathogenic (Jan 29, 2018)	germline	curation	PubMed (1) [See all records that cite this PMID]
SCV001586988	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Dec 4, 2023)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 7505694, 21097845, 25363320, 23974870, 28492532
SCV002657040	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Pathogenic (Nov 24, 2020)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 23974870, 7505694, 8663008 Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	research, curation
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Regulation of Cl-/ HCO3- exchange by cystic fibrosis transmembrane conductance regulator expressed in NIH 3T3 and HEK 293 cells.

Lee MG, Wigley WC, Zeng W, Noel LE, Marino CR, Thomas PJ, Muallem S.

J Biol Chem. 1999 Feb 5;274(6):3414-21.

PubMed [citation]

PMID:: 9920885

A protein sequence that can encode native structure by disfavoring alternate conformations.

Wigley WC, Corboy MJ, Cutler TD, Thibodeau PH, Oldan J, Lee MG, Rizo J, Hunt JF, Thomas PJ.

Nat Struct Biol. 2002 May;9(5):381-8.

PubMed [citation]

PMID:: 11938353

See all PubMed Citations (10)

Details of each submission

From CFTR2 - CFTR2, SCV000071514.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	research	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000697038.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Mendelics, SCV000886189.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Counsyl, SCV001132149.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From CFTR-France, SCV001169322.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001586988.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

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). 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: 23974870). For these reasons, this variant has been classified as Pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Ambry Genetics, SCV002657040.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

The p.P205S pathogenic mutation (also known as c.613C>T and 745C>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). Based on the supporting evidence, p.P205S is classified as a disease-causing mutation.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Oct 13, 2024

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