NM_000492.4(CFTR):c.2900T>C (p.Leu967Ser) AND not provided

Germline classification:: Conflicting interpretations of pathogenicity (10 submissions)
Last evaluated:: May 5, 2023
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:: RCV000587447.44

Allele description [Variation Report for NM_000492.4(CFTR):c.2900T>C (p.Leu967Ser)]

NM_000492.4(CFTR):c.2900T>C (p.Leu967Ser)

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.2900T>C (p.Leu967Ser)

HGVS:

NC_000007.14:g.117603774T>C
NG_016465.4:g.142991T>C
NM_000492.4:c.2900T>CMANE SELECT
NP_000483.3:p.Leu967Ser
NP_000483.3:p.Leu967Ser
LRG_663t1:c.2900T>C
LRG_663:g.142991T>C
LRG_663p1:p.Leu967Ser
NC_000007.13:g.117243828T>C
NM_000492.3:c.2900T>C
P13569:p.Leu967Ser

Protein change:

L967S

Links:

UniProtKB: P13569#VAR_009905; dbSNP: rs1800110

NCBI 1000 Genomes Browser:

rs1800110

Molecular consequence:

NM_000492.4:c.2900T>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
SCV000331169	Eurofins Ntd Llc (ga)	criteria provided, single submitter (EGL ClinVar v180209 classification definitions)	Uncertain significance (Aug 23, 2018)	germline	clinical testing	Citation Link,
SCV000567994	GeneDx	criteria provided, single submitter (GeneDx Variant Classification (06012015))	Uncertain significance (Jun 14, 2017)	germline	clinical testing	Citation Link,
SCV000603067	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process)	Pathogenic (Jul 27, 2020)	germline	clinical testing	Citation Link,
SCV000889303	Quest Diagnostics Nichols Institute San Juan Capistrano	criteria provided, single submitter (Quest Diagnostics criteria)	Uncertain significance (May 5, 2023)	unknown	clinical testing	PubMed (25) [See all records that cite these PMIDs] 28544683, 26898888, 22271776, 29589582, 29805046, 25963003, 31088717, 34996830, 33946859, 33768849, 32784480, 34782259, 34426522, 21520337, 23951356, 25033378, 10970190, 24586523, 27214204, 25346962, 21184098, 15858154, 20837875, 24451227, 26467025
SCV001715965	Mayo Clinic Laboratories, Mayo Clinic	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Oct 26, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001951065	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
SCV001972039	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
SCV001978707	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen - VKGL Data-share Consensus	no assertion criteria provided	Uncertain significance	germline	clinical testing
SCV002009132	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Nov 3, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004160966	CeGaT Center for Human Genetics Tuebingen	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2)	Uncertain significance (Apr 1, 2022)	germline	clinical testing	Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	2	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	not provided	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
not provided	germline	unknown	24	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Comprehensive genetic study of cystic fibrosis in Slovak patients in 25 years of genetic diagnostics.

Soltysova A, Tothova Tarova E, Ficek A, Baldovic M, Polakova H, Kayserova H, Kadasi L.

Clin Respir J. 2018 Mar;12(3):1197-1206. doi: 10.1111/crj.12651. Epub 2017 Jun 5.

PubMed [citation]

PMID:: 28544683

Cystic fibrosis - characterization of the adult population in Portugal.

Silva A, Amorim A, Azevedo P, Lopes C, Gamboa F.

Rev Port Pneumol (2006). 2016 May-Jun;22(3):141-5. doi: 10.1016/j.rppnen.2015.12.010. Epub 2016 Feb 15.

PubMed [citation]

PMID:: 26898888

See all PubMed Citations (26)

Details of each submission

From Eurofins Ntd Llc (ga), SCV000331169.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	10	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		10	not provided	not provided	not provided

From GeneDx, SCV000567994.4

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

Description

The L967S variant in the CFTR gene has been reported previously in association with pancreatitis, rhinosinusitis, and nonclassic cystic fibrosis, in affected individuals who were either heterozygous for the L967S variant and no second CFTR variant, or who were heterozygous for the L967S variant and a second CFTR variant (Wang et al., 2000; Groman et al., 2002; Bishop et al., 2005; LaRusch et al., 2014). The L967S variant was not observed at any significant frequency in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The L967S variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved in mammals. Functional studies show L967S has normal chloride, but selectively alters the bicarbonate permeation of the CFTR channel (LaRusch et al., 2014). We interpret L967S 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 ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories, SCV000603067.4

#	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.2900T>C; p.Leu967Ser variant (rs1800110) is reported in the literature in multiple individuals affected with CFTR-related disorders, including some with a pathogenic variant in trans (Bishop 2005, Cohn 2005, Masson 2013, Wang 2000). This variant is observed at a higher frequency in individuals diagnosed with pancreatitis compared to unaffected individuals (odds ratio >5, p<0.05) (LaRusch 2014). The p.Leu967Ser variant is reported in ClinVar (Variation ID: 219537), and it is found in the general population with an overall allele frequency of 0.07% (199/282620 alleles) in the Genome Aggregation Database. The leucine at residue 967 is moderately conserved, and computational algorithms (SIFT, PolyPhen-2) predict that this variant is deleterious. Functional assays suggest this variant has a modest or no effect on chloride channel activity, but exhibits decreased bicarbonate transport (LaRusch 2014, Raraigh 2018). Based on available information, this variant is not expected to cause classic cystic fibrosis, but is considered to be pathogenic-mild for CFTR-related disorders. References: Bishop MD et al. The cystic fibrosis transmembrane conductance regulator gene and ion channel function in patients with idiopathic pancreatitis. Hum Genet. 2005 Dec;118(3-4):372-81. Cohn JA et al. Increased risk of idiopathic chronic pancreatitis in cystic fibrosis carriers. Hum Mutat. 2005 Oct;26(4):303-7. 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. 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. 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. Wang X et al. Mutation in the gene responsible for cystic fibrosis and predisposition to chronic rhinosinusitis in the general population. JAMA. 2000 Oct 11;284(14):1814-9.

#	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 Quest Diagnostics Nichols Institute San Juan Capistrano, SCV000889303.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (25)

Description

This variant has been reported, alone or with a CF causing mutation, in patients with atypical presentations including oligospermia and idiopathic pancreatitis (PMIDs: 31088717 (2019), 29589582 (2017), 25033378 (2014), 23951356 (2013), 21520337 (2011), 10970190 (2000)). It has also been reported in individuals with CF or CF-like symptoms, including asthma and allergic bronchopulmonary aspergillosis (ABPA) (PMIDs: 33768849 (2021), 34782259 (2021)). In addition, this variant occurring with a second pathogenic CFTR variant has not been associated with pancreatic insufficiency or persistent Pseudomonas aeruginosa colonization (PMID: 27214204 (2016), 32784480 (2020)).

#	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 Mayo Clinic Laboratories, Mayo Clinic, SCV001715965.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	14	not provided	not provided	clinical testing	PubMed (1)

Description

PM2, PM3_strong

#	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		14	not provided	not provided	not provided

From Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ - VKGL Data-share Consensus, SCV001951065.1

#	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, SCV001972039.1

#	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 Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen - VKGL Data-share Consensus, SCV001978707.1

#	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 Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden, SCV002009132.3

#	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	not provided	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From CeGaT Center for Human Genetics Tuebingen, SCV004160966.10

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

Description

CFTR: PM3, PM2:Supporting, PS3:Supporting, PS4: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		2	not provided	not provided	not provided

Last Updated: Nov 3, 2024

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