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

Germline classification:: Conflicting interpretations of pathogenicity (9 submissions)
Last evaluated:: Nov 14, 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:: RCV000206091.36

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)

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
SCV000259453	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Oct 28, 2022)	germline	clinical testing	PubMed (13) [See all records that cite these PMIDs] 10970190, 12167682, 15858154, 16134171, 16193325, 21499205, 21520337, 23951356, 24586523, 25033378, 33768849, 29805046, 28492532
SCV000796460	Counsyl	criteria provided, single submitter (Counsyl Autosomal Recessive and X-Linked Classification Criteria (2018))	Uncertain significance (Dec 14, 2017)	unknown	clinical testing	PubMed (10) [See all records that cite these PMIDs] 28544683, 22271776, 26898888, 15858154, 7691344, 18195584, 21184098, 7525963, 12167682, 24586523 Citation Link,
SCV000886148	Mendelics	criteria provided, single submitter (Mendelics Assertion Criteria 2017)	Likely pathogenic (Nov 5, 2018)	unknown	clinical testing	Citation Link,
SCV001177923	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Uncertain significance (Jan 23, 2023)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 16134171, 23951356, 24451227, 24586523, 25033378, 29805046, 33768849 Citation Link,
SCV001905480	Johns Hopkins Genomics, Johns Hopkins University	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Aug 24, 2021)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 12167682, 25741868
SCV002507363	Genome Diagnostics Laboratory, The Hospital for Sick Children	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Jul 29, 2019)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002580890	MGZ Medical Genetics Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Aug 30, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004814228	North West Genomic Laboratory Hub, Manchester University NHS Foundation Trust	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Jul 31, 2020)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 29589582, 29805046, 25741868
SCV005045060	Clinical Genomics Laboratory, Washington University in St. Louis	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Nov 14, 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	2	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	yes	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	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Many deltaF508 heterozygote neonates with transient hypertrypsinaemia have a second, mild CFTR mutation.

Boyne J, Evans S, Pollitt RJ, Taylor CJ, Dalton A.

J Med Genet. 2000 Jul;37(7):543-7. No abstract available.

PubMed [citation]

PMID:: 10970190
PMCID:: PMC1734626

The cystic fibrosis transmembrane conductance regulator gene and ion channel function in patients with idiopathic pancreatitis.

Bishop MD, Freedman SD, Zielenski J, Ahmed N, Dupuis A, Martin S, Ellis L, Shea J, Hopper I, Corey M, Kortan P, Haber G, Ross C, Tzountzouris J, Steele L, Ray PN, Tsui LC, Durie PR.

Hum Genet. 2005 Dec;118(3-4):372-81. Epub 2005 Sep 29.

PubMed [citation]

PMID:: 16193325

See all PubMed Citations (23)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000259453.9

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (13)

Description

This sequence change replaces leucine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 967 of the CFTR protein (p.Leu967Ser). This variant is present in population databases (rs1800110, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with acute recurrent pancreatitis without lung disease, hypertrypsinemia without lung disease, idiopathic chronic pancreatitis, and/or suspected cystic fibrosis (PMID: 10970190, 12167682, 15858154, 16134171, 16193325, 21499205, 21520337, 23951356, 24586523, 25033378, 33768849). ClinVar contains an entry for this variant (Variation ID: 219537). 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 not expected to disrupt CFTR protein function. Experimental studies have shown that this missense change affects CFTR function (PMID: 29805046). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

#	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 Counsyl, SCV000796460.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (10)

#	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 Mendelics, SCV000886148.2

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

From Ambry Genetics, SCV001177923.5

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

Description

The p.L967S variant (also known as c.2900T>C), located in coding exon 17 of the CFTR gene, results from a T to C substitution at nucleotide position 2900. The leucine at codon 967 is replaced by serine, an amino acid with dissimilar properties. This variant has been reported in individuals with a second known pathogenic mutation and varying clinical presentations including: cystic fibrosis (CF), transient neonatal hypertrypsinemia, and non-classic CF; however, the phase of the alterations was not confirmed (Claustres M et al. Hum Mol Genet. 1993; 2(8):1209-1213; Boyne J et al. J Med Genet. 2000;37(7):543-547; Groman JD et al. N Engl J Med. 2002;347(6):401-407; Choi P et al. Clin Case Rep, 2021 Mar;9:1379-1382). Several studies have reported this alteration in individuals with pancreatitis, some with additional alterations in SPINK1 and/or CFTR (Audrezet MP et al. Eur J Hum Genet. 2002;10(2):100-106; Cohn JA et al. Hum Mutat. 2005;26(4):303-307; Bishop MD et al. Hum Genet. 2005;118(3-4):372-381; Masson et al. PLoS ONE 2013; 8(8):e73522; LaRusch J et al. PLoS Genet., 2014 Jul;10:e1004376). One functional study showed that this alteration results in normal protein folding, glycosylation, and chloride channel activities, but HEK 293T cells expressing p.L967S have significantly altered bicarbonate permeability and conductance compared to wild-type (p<0.01) (LaRusch J et al. PLoS Genet., 2014 Jul;10:e1004376). In CFBE cells, chloride conductance for this variant was 74% of wild type (Raraigh KS et al. Am. J. Hum. Genet., 2018 Jun;102:1062-1077). The p.L967S alteration has been reported as a variant of varying clinical consequences (VVCC) (Sosnay PR et al. Pediatr. Clin. North Am., 2016 08;63:585-98; The Clinical and Functional TRanslation of CFTR (CFTR2); available at http://cftr2.org. Accessed March 29, 2018). This amino acid position is not well 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 Johns Hopkins Genomics, Johns Hopkins University, SCV001905480.1

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

Description

CFTR variant associated with varying clinical consequence. See www.CFTR2.org for phenotype information.

#	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 Genome Diagnostics Laboratory, The Hospital for Sick Children, SCV002507363.1

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

From MGZ Medical Genetics Center, SCV002580890.1

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

From North West Genomic Laboratory Hub, Manchester University NHS Foundation Trust, SCV004814228.1

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

Description

Criteria Codes: PM3_VStr 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

From Clinical Genomics Laboratory, Washington University in St. Louis, SCV005045060.1

#	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.2900T>C (p.Leu967Ser) variant has been reported in patients with chronic rhinosinusitis, chronic pancreatitis, or nonclassical cystic fibrosis (Bishop MD et al., PMID: 16193325; Cohen JA et al., PMID: 16134171; Groman JD et al., PMID: 12167682; LaRusch J et al., PMID: 25033378; Lucidi V et al., PMID: 21499205; Masson E et al., PMID: 23951356; Schrijver I et al., PMI: 15858154; Wang X et al., PMID: 11025834; Zietkiewicz E et al., PMID: 24586523). The majority of cases were compound heterozygous for the variant and a second variant confirmed in trans. Functional studies by one group demonstrated that p.Leu967Ser maintained 74% of CFTR function (Raraigh KS et al,. PMID: 29805046). LaRusch and colleagues showed that the variant does not impact CFTR expression, stability or chloride levels. Furthermore, they demonstrated that this and other variants not associated with typical CF alter the WNK1-SPAK activation pathway, changing CFTR permeability from a chloride to bicarbonate-preferring channel (LaRusch J et al., PMID: 25033378), indicative of an alternate disease mechanism. The highest population minor allele frequency in the population database genome aggregation database (v.2.1.1) is 0.10% in the European-Non-Finnish population. Computational predictors indicate that the variant is damaging, evidence that correlates with impact to CFTR function. This variant has been reported as a variant with varying clinical consequences in the CFTR2 database (http://cftr2.org). The variant has been reported in the ClinVar database as a pathogenic variant by one submitter, likely pathogenic by three submitters and a variant of uncertain significance by 17 submitters (ClinVar Variation ID: 219537). Due to limited information, and based on ACMG/AMP guidelines for variant interpretation (Richards S et al., PMID: 25741868), the clinical significance of this variant is uncertain at this time.

#	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 3, 2024

Relating variation to medicine