NM_000492.4(CFTR):c.2991G>C (p.Leu997Phe) AND not provided

This record was updated by the submitter. Please see the current version.

Germline classification:: Conflicting interpretations of pathogenicity (11 submissions)
Last evaluated:: Apr 1, 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:: RCV000078991.54

Allele description

NM_000492.4(CFTR):c.2991G>C (p.Leu997Phe)

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.2991G>C (p.Leu997Phe)

HGVS:

NC_000007.14:g.117610521G>C
NG_016465.4:g.149738G>C
NG_056128.2:g.3575G>C
NM_000492.4:c.2991G>CMANE SELECT
NP_000483.3:p.Leu997Phe
NP_000483.3:p.Leu997Phe
LRG_663t1:c.2991G>C
LRG_663:g.149738G>C
LRG_663p1:p.Leu997Phe
NC_000007.13:g.117250575G>C
NG_056128.1:g.3575G>C
NM_000492.3:c.2991G>C
P13569:p.Leu997Phe

Protein change:

L997F; LEU997PHE

Links:

UniProtKB: P13569#VAR_000227; OMIM: 602421.0124; dbSNP: rs1800111

NCBI 1000 Genomes Browser:

rs1800111

Molecular consequence:

NM_000492.4:c.2991G>C - 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
SCV000226875	Eurofins Ntd Llc (ga)	criteria provided, single submitter (EGL Classification Definitions)	Pathogenic (Aug 12, 2016)	germline	clinical testing	Citation Link,
SCV000493335	CeGaT Center for Human Genetics Tuebingen	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2)	Pathogenic (Apr 1, 2024)	germline	clinical testing	Citation Link,
SCV000589481	GeneDx	criteria provided, single submitter (GeneDx Variant Classification (06012015))	Uncertain significance (Dec 27, 2018)	germline	clinical testing	Citation Link,
SCV000601084	Quest Diagnostics Nichols Institute San Juan Capistrano	criteria provided, single submitter (Quest Diagnostics criteria)	Uncertain significance (Aug 2, 2023)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000602993	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2024)	Uncertain significance (Oct 27, 2023)	germline	clinical testing	Citation Link,
SCV001714240	Mayo Clinic Laboratories, Mayo Clinic	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Dec 16, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001744100	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen - VKGL Data-share Consensus	no assertion criteria provided	Uncertain significance	germline	clinical testing
SCV001928674	Genome Diagnostics Laboratory, University Medical Center Utrecht - VKGL Data-share Consensus See additional submitters Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	no assertion criteria provided	Uncertain significance	germline	clinical testing
SCV001951969	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ - VKGL Data-share Consensus See additional submitters Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	no assertion criteria provided	Uncertain significance	germline	clinical testing
SCV001968505	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center - VKGL Data-share Consensus See additional submitters Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	no assertion criteria provided	Uncertain significance	germline	clinical testing
SCV003831649	Revvity Omics, Revvity	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Jul 31, 2023)	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	15	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	20	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

A Standardized DNA Variant Scoring System for Pathogenicity Assessments in Mendelian Disorders.

Karbassi I, Maston GA, Love A, DiVincenzo C, Braastad CD, Elzinga CD, Bright AR, Previte D, Zhang K, Rowland CM, McCarthy M, Lapierre JL, Dubois F, Medeiros KA, Batish SD, Jones J, Liaquat K, Hoffman CA, Jaremko M, Wang Z, Sun W, Buller-Burckle A, et al.

Hum Mutat. 2016 Jan;37(1):127-34. doi: 10.1002/humu.22918. Epub 2015 Oct 29.

PubMed [citation]

PMID:: 26467025
PMCID:: PMC4737317

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee.

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Details of each submission

From Eurofins Ntd Llc (ga), SCV000226875.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	20	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	germline	unknown	not provided	not provided	not provided		20	not provided	not provided	not provided

From CeGaT Center for Human Genetics Tuebingen, SCV000493335.30

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	15	not provided	not provided	clinical testing	not provided

Description

CFTR: PM3:Very Strong, PM2:Supporting, 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		15	not provided	not provided	not provided

From GeneDx, SCV000589481.3

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

Description

The L997F variant in the CFTR gene has been reported previously in trans with another pathogenic CFTR variant in individuals with cystic fibrosis and atypical cystic fibrosis, as well as in asymptomatic individuals (Lucarelli et al., 2010; Strom et al., 2011; Schippa et al., 2013). It has been suggested that the presence of the R117L variant in cis with L997F as a complex allele may in part explain the variable phenotype observed in individuals with the L997F variant (Lucarelli et al., 2010). The L997F variant is observed in 59/10,146 (0.58%) alleles from individuals of Ashkenazi Jewish background in large population cohorts (Lek et al., 2016). The L997F variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Functional studies demonstrated that the L997F variant was associated with somewhat reduced chloride transport (VanGoor et al., 2014). We interpret L997F as a variant of uncertain significance.

#	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 Quest Diagnostics Nichols Institute San Juan Capistrano, SCV000601084.3

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

Description

The CFTR c.2991G>C (p.Leu997Phe) variant has been reported with other CFTR variants in the published literature in individuals with Cystic Fibrosis (CF) (PMID: 1379210 (1992), 9921909 (1998), 17572159 (2008), 20706124, 21804385 (2011), 23613805 (2013), 27738188 (2016)) and CF-related disorders including pancreatitis (PMID: 10801389 (2000), 18501000 (2008), 20460946 (2010), 23951356 (2013), 29589582 (2018)), bronchiectasis (PMID: 9921909 (1998)) and congenital bilateral absence of the vas deferens (CBAVD) (PMID: 9272157 (1997), 10875853 (2000), 26911355 (2016)). This variant is also found to occur as part of a complex allele p.[R117L; L997F] and is often associated with a more severe phenotype in individuals with cystic fibrosis (PMID: 25910067 (2015)). This variant has also been reported in asymptomatic individuals (PMID: 12014388 (2002), 15857421 (2005)). Functional studies indicated that this variant results in reduction of CFTR chloride transport activity, channel diameter and alters bicarbonate permeability (PMID: 25824995 (2015), 23891399 (2014), 25033378 (2014)). The frequency of this variant in the general population, 0.0099 (115/11590 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant.

#	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 ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories, SCV000602993.6

#	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.2991G>C; p.Leu997Phe variant (rs1800111) has been identified in multiple individuals diagnosed with CFTR-related disorders (Bergougnoux 2015, Gallati 2009, Gomez-Lira 2000, Hamoir 2013, Lucarelli 2010, Masson 2013, Pelletier 2010), but case control studies disagree if this variant is enriched in pancreatitis patients (LaRusch 2014, Gomez-Lira 2000). In addition, individuals homozygous for this variant have been reported to be clinically asymptomatic (Derichs 2005, Stanke 2008, Terlizzi 2017). Functional characterization of the variant protein indicates a reduction in the CFTR chloride transport activity (Bergougnoux 2015, Sosnay 2013, Van Goor 2014), but at a level unlikely to cause cystic fibrosis (Sosnay 2013, Strom 2011). This variant is reported in ClinVar (Variation ID: 7229) and is observed in the general population at a frequency of 0.22% (627/282204 alleles, including 3 homozygotes) in the Genome Aggregation Database. The leucine at codon 997 is highly conserved, but computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.625). Due to the conflicting information regarding this variant, its clinical significance cannot be determined with certainty. References: Bergougnoux A et al. Should diffuse bronchiectasis still be considered a CFTR-related disorder? J Cyst Fibros. 2015; 14(5):646-53. PMID: 25797027. Derichs N et al. Homozygosity for L997F in a child with normal clinical and chloride secretory phenotype provides evidence that this cystic fibrosis transmembrane conductance regulator mutation does not cause cystic fibrosis. Clin Genet. 2005; 67(6):529-31. PMID: 15857421. Gallati S et al Cystic fibrosis transmembrane conductance regulator mutations in azoospermic and oligospermic men and their partners. Reprod Biomed Online. 2009; 19(5):685-94. PMID: 20021716. Gomez-Lira M et al. High frequency of cystic fibrosis transmembrane regulator mutation L997F in patients with recurrent idiopathic pancreatitis and in newborns with hypertrypsinemia. Am J Hum Genet. 2000; 66(6):2013-4. PMID: 10801389. Hamoir C et al. Clinical and morphological characteristics of sporadic genetically determined pancreatitis as compared to idiopathic pancreatitis: higher risk of pancreatic cancer in CFTR variants. Digestion. 2013; 87(4):229-39. PMID: 23751316. LaRusch J et al. Mechanisms of CFTR functional variants that impair regulated bicarbonate permeation and increase risk for pancreatitis but not for cystic fibrosis. PLoS Genet. 2014 10(7):e1004376. PMID: 25033378. Lucarelli M et al. A new complex allele of the CFTR gene partially explains the variable phenotype of the L997F mutation. Genet Med. 2010; 12(9):548-55. PMID: 20706124. Masson E et al. A conservative assessment of the major genetic causes of idiopathic chronic pancreatitis: data from a comprehensive analysis of PRSS1, SPINK1, CTRC and CFTR genes in 253 young French patients. PLoS One. 2013; 8(8):e73522. PMID: 23951356. Pelletier A et al. CFTR gene mutation in patients with apparently idiopathic pancreatitis: lack of phenotype-genotype correlation. Pancreatology. 2010; 10(2-3):158-64. PMID: 20460946. Sosnay PR et al. Defining the disease liability of variants in the cystic fibrosis transmembrane conductance regulator gene. Nat Genet. 2013; 45(10):1160-7. PMID: 23974870. Stanke F et al. Diversity of the basic defect of homozygous CFTR mutation genotypes in humans. J Med Genet. 2008; 45(1):47-54. PMID: 18178635. Strom C et al. The dangers of including nonclassical cystic fibrosis variants in population-based screening panels: p.L997F, further genotype/phenotype correlation data. Genet Med. 2011; 13(12):1042-4. PMID: 21804385. Terlizzi V et al. Genotype-phenotype correlation and functional studies in patients with cystic fibrosis bearing CFTR complex alleles. J Med Genet. 2017 Apr;54(4):224-235. PMID: 27738188. Van Goor F et al. Effect of ivacaftor on CFTR forms with missense mutations associated with defects in protein processing or function. J Cyst Fibros. 2014; 13(1):29-36. PMID: 23891399.

#	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 Mayo Clinic Laboratories, Mayo Clinic, SCV001714240.2

#	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	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen - VKGL Data-share Consensus, SCV001744100.3

#	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	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Genome Diagnostics Laboratory, University Medical Center Utrecht - VKGL Data-share Consensus, SCV001928674.1

#	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	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ - VKGL Data-share Consensus, SCV001951969.1

#	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	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center - VKGL Data-share Consensus, SCV001968505.1

#	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	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Revvity Omics, Revvity, SCV003831649.2

#	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	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Jul 29, 2024

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