NM_000492.4(CFTR):c.3038C>T (p.Pro1013Leu) AND Cystic fibrosis

Germline classification:: Conflicting interpretations of pathogenicity (7 submissions)
Last evaluated:: Jan 11, 2024
Review status:: criteria provided, conflicting classifications

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:: RCV000577169.11

Allele description [Variation Report for NM_000492.4(CFTR):c.3038C>T (p.Pro1013Leu)]

NM_000492.4(CFTR):c.3038C>T (p.Pro1013Leu)

Genes:

CFTR:CF transmembrane conductance regulator [Gene - OMIM - HGNC]
LOC111674472:DNase I hypersensitive sites in introns 16 and 17a of CFTR [Gene]

Variant type:

single nucleotide variant

Cytogenetic location:

7q31.2

Genomic location:

Preferred name:

NM_000492.4(CFTR):c.3038C>T (p.Pro1013Leu)

HGVS:

NC_000007.14:g.117610568C>T
NG_016465.4:g.149785C>T
NG_056128.2:g.3622C>T
NM_000492.4:c.3038C>TMANE SELECT
NP_000483.3:p.Pro1013Leu
NP_000483.3:p.Pro1013Leu
LRG_663t1:c.3038C>T
LRG_663:g.149785C>T
LRG_663p1:p.Pro1013Leu
NC_000007.13:g.117250622C>T
NM_000492.3:c.3038C>T
P13569:p.Pro1013Leu

Protein change:

P1013L

Links:

UniProtKB: P13569#VAR_000230; dbSNP: rs193922516

NCBI 1000 Genomes Browser:

rs193922516

Molecular consequence:

NM_000492.4:c.3038C>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
SCV000679367	ClinVar Staff, National Center for Biotechnology Information (NCBI)	no classification provided	not provided	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV000791585	Counsyl	criteria provided, single submitter (Counsyl Autosomal Recessive and X-Linked Classification Criteria (2018))	Uncertain significance (May 12, 2017)	unknown	clinical testing	PubMed (5) [See all records that cite these PMIDs] 16436643, 23613805, 11278813, 12439892, 9521595 Citation Link,
SCV001338832	Molecular Genetics Laboratory, BC Children's and BC Women's Hospitals	no assertion criteria provided (ACMG Guidelines, 2015)	Uncertain significance (Jan 30, 2020)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001781370	Genome-Nilou Lab	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Jul 14, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002246801	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Jan 11, 2024)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 9521595, 17594398, 23613805, 34860163, 11278813, 28492532
SCV002753216	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Uncertain significance (Sep 12, 2019)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 11278813, 11446424, 12439892, 16436643, 17594398, 23613805, 9521595 Citation Link,
SCV004814233	North West Genomic Laboratory Hub, Manchester University NHS Foundation Trust	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Nov 6, 2019)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

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	clinical testing, literature only
not provided	germline	no	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	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

The Genetic Analysis of Cystic Fibrosis Patients With Seven Novel Mutations in the CFTR Gene in the Central Anatolian Region of Turkey.

Erdoğan M, Köse M, Pekcan S, Hangül M, Balta B, Kiraz A, Akıncı Gönen G, Zamani AG, Yıldırım MS, Ramaslı Gürsoy T, Ezgu F, Şişmanlar Eyüpoğlu T, Tana Aslan A.

Balkan Med J. 2021 Nov;38(6):357-364. doi: 10.5152/balkanmedj.2021.21199.

PubMed [citation]

PMID:: 34860163
PMCID:: PMC8880976

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

See all PubMed Citations (10)

Details of each submission

From ClinVar Staff, National Center for Biotechnology Information (NCBI), SCV000679367.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	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 Counsyl, SCV000791585.1

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

#	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 Molecular Genetics Laboratory, BC Children's and BC Women's Hospitals, SCV001338832.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	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 Genome-Nilou Lab, SCV001781370.1

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

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	no	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV002246801.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 1013 of the CFTR protein (p.Pro1013Leu). This variant is present in population databases (rs193922516, gnomAD 0.02%). This missense change has been observed in individual(s) with cystic fibrosis (PMID: 9521595, 17594398, 23613805, 34860163). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 53634). 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: 11278813). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely 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, SCV002753216.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (7)

Description

The p.P1013L variant (also known as c.3038C>T), located in coding exon 19 of the CFTR gene, results from a C to T substitution at nucleotide position 3038. The proline at codon 1013 is replaced by leucine, an amino acid with similar properties. This variant was initially reported in a Turkish individual with cystic fibrosis (CF), elevated sweat chloride levels, and an intronic variant confirmed in trans (Onay T et al. Hum. Genet., 1998 Feb;102:224-30). It has also been reported in two siblings with a diagnosis of CF; both siblings were also heterozygous for p.F508del (phase not provided) (Schippa S et al. PLoS ONE, 2013 Apr;8:e61176). In a newborn with an elevated immunoreactive trypsinogen and normal sweat chloride levels, this variant was identified in conjunction with p.F508del; at four years, this individual was asymptomatic with normal sweat chloride levels, normal height and weight, and negative bacterial cultures (Narzi L et al. Clin. Genet., 2007 Jul;72:39-46). 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 available evidence to date, the clinical significance of this alteration remains unclear.

#	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 North West Genomic Laboratory Hub, Manchester University NHS Foundation Trust, SCV004814233.1

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

Description

Criteria Codes: PP3 PM3 PM1_Supp PM2

#	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

Last Updated: Sep 29, 2024

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