NM_000492.4(CFTR):c.2780T>C (p.Leu927Pro) AND Cystic fibrosis

Germline classification:: Pathogenic (5 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:: RCV000056371.9

Allele description [Variation Report for NM_000492.4(CFTR):c.2780T>C (p.Leu927Pro)]

NM_000492.4(CFTR):c.2780T>C (p.Leu927Pro)

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.2780T>C (p.Leu927Pro)

HGVS:

NC_000007.14:g.117603654T>C
NG_016465.4:g.142871T>C
NM_000492.4:c.2780T>CMANE SELECT
NP_000483.3:p.Leu927Pro
NP_000483.3:p.Leu927Pro
LRG_663t1:c.2780T>C
LRG_663:g.142871T>C
LRG_663p1:p.Leu927Pro
NC_000007.13:g.117243708T>C
NM_000492.3:c.2780T>C

Protein change:

L927P

Links:

dbSNP: rs397508435

NCBI 1000 Genomes Browser:

rs397508435

Molecular consequence:

NM_000492.4:c.2780T>C - 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
SCV000071510	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,
SCV000487119	Counsyl	criteria provided, single submitter (Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015))	Likely pathogenic (Oct 7, 2016)	unknown	clinical testing	PubMed (3) [See all records that cite these PMIDs] 23727931, 23891399, 23974870 mdi-5618_320494_Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015).pdf, Citation Link,
SCV000696924	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Jun 13, 2017)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 7526927, 21416780, 25826586, 23891399, 23974870 LabCorp Variant Classification Summary - May 2015.docx, Citation Link,
SCV001169513	CFTR-France	criteria provided, single submitter (Claustres M et al. (Hum Mutat 2017))	Pathogenic (Jul 3, 2015)	germline	curation	PubMed (1) [See all records that cite this PMID]
SCV002746349	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Pathogenic (Jul 8, 2022)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 17481968, 7526927 Citation Link

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Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
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

Citations

PubMed

A functional CFTR assay using primary cystic fibrosis intestinal organoids.

Dekkers JF, Wiegerinck CL, de Jonge HR, Bronsveld I, Janssens HM, de Winter-de Groot KM, Brandsma AM, de Jong NW, Bijvelds MJ, Scholte BJ, Nieuwenhuis EE, van den Brink S, Clevers H, van der Ent CK, Middendorp S, Beekman JM.

Nat Med. 2013 Jul;19(7):939-45. doi: 10.1038/nm.3201. Epub 2013 Jun 2.

PubMed [citation]

PMID:: 23727931

CFTR allelic heterogeneity in Mexican patients with cystic fibrosis: implications for molecular screening.

Chávez-Saldaña M, Yokoyama E, Lezana JL, Carnevale A, Macías M, Vigueras RM, López M, Orozco L.

Rev Invest Clin. 2010 Nov-Dec;62(6):546-52.

PubMed [citation]

PMID:: 21416780

See all PubMed Citations (8)

Details of each submission

From CFTR2 - CFTR2, SCV000071510.4

#	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 Counsyl, SCV000487119.2

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

#	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 Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000696924.1

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

Description

Variant summary: The CFTR c.2780T>C (p.Leu927Pro) variant involves the alteration of a highly conserved nucleotide and 5/5 in silico tools predict a damaging outcome. The deleterious effect of this change has been confirmed by functional studies where L927P was shown to have a reduce maturation level and severely affected Cl- transport. The variant is absent from the control population datasets of ExAC and gnomAD (~121324 and 216186 chrs tested) but was identified in multiple CF patients in compound heterozygosity with known pathogenic mutations. Multiple published reports and clinical diagnostic laboratories/reputable databases classified this variant as severe mutation/Pathogenic. Taking together, the 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 CFTR-France, SCV001169513.1

#	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 Ambry Genetics, SCV002746349.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

The p.L927P pathogenic mutation (also known as c.2780T>C), located in coding exon 17 of the CFTR gene, results from a T to C substitution at nucleotide position 2780. The leucine at codon 927 is replaced by proline, an amino acid with similar properties. This variant has been reported in multiple individuals with an elevated sweat chloride level in The Clinical and Functional TRanslation of CFTR (CFTR2) database (available at http://cftr2.org. Accessed 07/08/2022). This variant has also been reported in conjunction with other CFTR pathogenic mutations in multiple individuals with cystic fibrosis (Hermans CJ et al. Hum Mol Genet, 1994 Jul;3:1199-200; Storm K et al. J Cyst Fibros, 2007 Nov;6:371-5). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted 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: May 19, 2024

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