NM_000492.4(CFTR):c.14C>T (p.Pro5Leu) AND not provided

Germline classification:: Pathogenic/Likely pathogenic (5 submissions)
Last evaluated:: Jun 26, 2024
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV000727666.29

Allele description [Variation Report for NM_000492.4(CFTR):c.14C>T (p.Pro5Leu)]

NM_000492.4(CFTR):c.14C>T (p.Pro5Leu)

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.14C>T (p.Pro5Leu)

HGVS:

NC_000007.14:g.117480108C>T
NG_016465.4:g.19325C>T
NG_056120.2:g.4138C>T
NM_000492.4:c.14C>TMANE SELECT
NP_000483.3:p.Pro5Leu
NP_000483.3:p.Pro5Leu
LRG_663t1:c.14C>T
LRG_663:g.19325C>T
LRG_663p1:p.Pro5Leu
NC_000007.13:g.117120162C>T
NG_056120.1:g.4138C>T
NM_000492.3:c.14C>T
NM_000492.4:c.14C>T

Protein change:

P5L

Links:

dbSNP: rs193922501

NCBI 1000 Genomes Browser:

rs193922501

Molecular consequence:

NM_000492.4:c.14C>T - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000854974	Eurofins Ntd Llc (ga)	criteria provided, single submitter (EGL Classification Definitions 2015)	Likely pathogenic (Nov 20, 2017)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 21520337, 21983161, 9439669 Citation Link,
SCV001469497	Quest Diagnostics Nichols Institute San Juan Capistrano	criteria provided, single submitter (Quest Diagnostics criteria)	likely pathogenic (Jun 26, 2024)	unknown	clinical testing	PubMed (31) [See all records that cite these PMIDs] 33374015, 30134826, 30046002, 28603918, 27264265, 23430892, 21520337, 19318035, 15758663, 11938439, 29805046, 31328366, 20351098, 28736296, 25754095, 25658530, 21983161, 18306312, 17594398, 17594397, 25910067, 17235394, 9439669, 19724303, 17331079, 20351101, 19897426, 17137500, 34426522, 34996830, 26467025
SCV002757301	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Likely pathogenic (Jun 1, 2022)	germline	clinical testing	Citation Link,
SCV002821843	CeGaT Center for Human Genetics Tuebingen	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2)	Pathogenic (Nov 1, 2022)	germline	clinical testing	Citation Link,
SCV004562363	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2024)	Pathogenic (Oct 4, 2023)	germline	clinical testing	Citation Link

Help

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	1	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	1	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Andrological findings in infertile men with two (biallelic) CFTR mutations: results of a multicentre study in Germany and Austria comprising 71 patients.

Rudnik-Schöneborn S, Messner M, Vockel M, Wirleitner B, Pinggera GM, Witsch-Baumgartner M, Murtinger M, Kliesch S, Swoboda M, Sänger N, Zschocke J, Tüttelmann F.

Hum Reprod. 2021 Feb 18;36(3):551-559. doi: 10.1093/humrep/deaa348.

PubMed [citation]

PMID:: 33374015

Trans-heterozygosity for mutations enhances the risk of recurrent/chronic pancreatitis in patients with Cystic Fibrosis.

Sofia VM, Surace C, Terlizzi V, Da Sacco L, Alghisi F, Angiolillo A, Braggion C, Cirilli N, Colombo C, Di Lullo A, Padoan R, Quattrucci S, Raia V, Tuccio G, Zarrilli F, Tomaiuolo AC, Novelli A, Lucidi V, Lucarelli M, Castaldo G, Angioni A.

Mol Med. 2018 Jul 27;24(1):38. doi: 10.1186/s10020-018-0041-6.

PubMed [citation]

PMID:: 30134826
PMCID:: PMC6062922

See all PubMed Citations (31)

Details of each submission

From Eurofins Ntd Llc (ga), SCV000854974.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	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	germline	unknown	not provided	not provided	not provided		1	not provided	not provided	not provided

From Quest Diagnostics Nichols Institute San Juan Capistrano, SCV001469497.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (31)

Description

The CFTR c.14C>T (p.Pro5Leu) variant is associated with a variable phenotype (see CFTR2 (http://cftr2.org/)). In the published literature, this variant has been reported in individuals with cystic fibrosis (PMIDs: 25658530 (2015), 25754095 (2015), 21983161 (2012), 19724303 (2010), 17331079 (2007), 17137500 (2006), 9439669 (1997)), atypical/mild CF symptoms (PMIDs: 31328366 (2019), 21983161 (2012), 19318035 (2009), 17594397 (2007)), and CFTR-related disorders (PMIDs: 34996830 (2022), 33374015 (2020), 27264265 (2016), 21520337 (2011), 15758663 (2005), 11938439 (2002)). Functional studies indicate this variant has deleterious effects on CFTR protein expression and ion channel activity (PMIDs: 29805046 (2018), 18306312 (2008), 17235394 (2007)). The frequency of this variant in the general population, 0.000054 (7/128930 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Based on the available information, this variant is classified as likely pathogenic.

#	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 GeneDx, SCV002757301.1

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

Description

Published functional studies demonstrate a damaging effect on chloride channel activity, protein maturation, and cellular localization (Thelin 2007, Gene 2008, Han 2018, Raraigh 2018); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Classified as a variant of varying clinical consequence in a well-curated database (CFTR2); This variant is associated with the following publications: (PMID: 31036917, 34426522, 29805046, 31328366, 20351101, 20351098, 17235394, 9439669, 25735457, 18306312, 23430892, 25910067, 30134826, 28736296, 27264265, 19897426, 19318035, 17594398, 17331079, 17137500, 33572515, 30046002, 25754095, 25658530, 31776420, 15758663, 21520337, 11938439, 17594397, 19724303, 21983161)

#	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 CeGaT Center for Human Genetics Tuebingen, SCV002821843.14

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

Description

CFTR: PM3:Very Strong, PM2, PS3:Supporting

#	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		1	not provided	not provided	not provided

From ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories, SCV004562363.1

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

Description

The CFTR c.14C>T; p.Pro5Leu variant (rs193922501) is described as a variant of varying clinical consequences (CFTR2 database). It has been observed in trans with a pathogenic severe variant (i.e. F508del) in individuals who were either asymptomatic, had atypical/mild cystic fibrosis, or were diagnosed with pancreatic sufficient or insufficient cystic fibrosis (CFTR2 database, Casals 1997, Gene 2008, Narzi 2007, Schneider 2007, Spicuzza 2012). Functional characterization of the variant indicates a failure to generate mature CFTR protein and localization to the plasma membrane, and has 10-25% function as wild type protein (Gene 2008, Raraigh 2018, Thelin 2007). This variant is reported in ClinVar (Variation ID: 35824). It is found in the general population with a low overall allele frequency of 0.002% (7/282536 alleles) in the Genome Aggregation Database. The proline at codon 5 is well conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Based on available information, this variant is classified as pathogenic with varying clinical consequences. REFERENCES CFTR2: https://www.cftr2.org/ Casals T et al. High heterogeneity for cystic fibrosis in Spanish families: 75 mutations account for 90% of chromosomes. Hum Genet. 1997 Dec;101(3):365-70. Gene GG et al. N-terminal CFTR missense variants severely affect the behavior of the CFTR chloride channel. Hum Mutat. 2008 May;29(5):738-49. Narzi L et al. Does cystic fibrosis neonatal screening detect atypical CF forms? Extended genetic characterization and 4-year clinical follow-up. Clin Genet. 2007 Jul;72(1):39-46. Schneider M et al. Large deletions in the CFTR gene: clinics and genetics in Swiss patients with CF. Clin Genet. 2007 Jul;72(1):30-8. Raraigh KS et al. Functional Assays Are Essential for Interpretation of Missense Variants Associated with Variable Expressivity. Am J Hum Genet. 2018 Jun 7;102(6):1062-1077. Spicuzza L et al. Mild cystic fibrosis in patients with the rare P5L CFTR mutation. J Cyst Fibros. 2012 Jan;11(1):30-3. Thelin WR et al. Direct interaction with filamins modulates the stability and plasma membrane expression of CFTR. J Clin Invest. 2007 Feb;117(2):364-74.

#	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: Nov 24, 2024

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