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

gnomAD frequency: 0.00106  dbSNP: rs1800110

Total submissions: 24

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000206091	SCV000259453	uncertain significance	Cystic fibrosis	2022-10-28	criteria provided, single submitter	clinical testing	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.
Eurofins Ntd Llc (ga)	RCV000587447	SCV000331169	uncertain significance	not provided	2018-08-23	criteria provided, single submitter	clinical testing
GeneDx	RCV000587447	SCV000567994	uncertain significance	not provided	2017-06-14	criteria provided, single submitter	clinical testing	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.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000587447	SCV000603067	pathogenic	not provided	2020-07-27	criteria provided, single submitter	clinical testing	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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000664323	SCV000696932	uncertain significance	not specified	2023-09-18	criteria provided, single submitter	clinical testing	Variant summary: CFTR c.2900T>C (p.Leu967Ser) results in a non-conservative amino acid change located in the ABC transporter type 1, transmembrane domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00072 in 255940 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in CFTR causing CFTR-Related Diseases (0.00072 vs 0.013), allowing no conclusion about variant significance. c.2900T>C has been reported in the literature in individuals affected with Cystic Fibrosis, CBAVD, non-classic CF, pancreatitis, and in a fetus with bowel anomalies. Several patients with pancreatitis were also found to carry another variant in CFTR or in other genes such as SPINK1, typically N34S, which is a known risk variant for pancreatitis. This variant also co-occurred in cis with another pathogenic variant in the CFTR gene in a fetus who had a compound heterozygous genotype [p.Phe508del/c.3191_3192ins16 (de Becdelivre_2011)]suggesting that L967S was not causative in this patient and is unlikely to be pathogenic in the autosomal recessive Mendelian inheritance pattern. In contrast, case-control studies (example, LaRusch_2014) suggest that L967S may increase the risk of developing pancreatitis (odds ratio=6.87 (p-value 0.002); with further increased odds ratio of 11.17 (p-value 0.014) in patients with co-occurring SPINK1 variant N34S. An in vitro functional study reported that this missense change does not affect CFTR expression, stability, or chloride conductance, but has a mild effect on bicarbonate permeability and conductance with WNK1-SPAK activation in cell culture (LaRusch_2014). Another study indicated that L967S maintained approximately 74% of wild-type function (Raraigh_2018). These reports do not provide unequivocal conclusions about association of the variant with Cystic Fibrosis. The following publications have been ascertained in the context of this evaluation (PMID: 12167682, 7691344, 15858154, 16134171, 21184098, 21520337, 16193325, 11025834, 11938439, 21499205, 23951356, 24451227, 24586523, 25824995, 25963003, 18195584, 28544683, 29805046, 25033378, 29589582, 31088717, 32784480, 33946859, 33768849, 34996830). Fifteen clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 with conflicting assessments (VUS, n=11; pathogenic/likely pathogenic n=4). The CFTR2 database reports this variant as having varying consequences, indicating that clinical criteria alone should be used to diagnose individuals with this variant with CFTR-related phenotypes. Based on the evidence outlined above, the variant was classified as uncertain significance.
Counsyl	RCV000206091	SCV000796460	uncertain significance	Cystic fibrosis	2017-12-14	criteria provided, single submitter	clinical testing
Mendelics	RCV000206091	SCV000886148	likely pathogenic	Cystic fibrosis	2018-11-05	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000587447	SCV000889303	uncertain significance	not provided	2023-05-05	criteria provided, single submitter	clinical testing	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)).
Ambry Genetics	RCV000206091	SCV001177923	uncertain significance	Cystic fibrosis	2023-01-23	criteria provided, single submitter	clinical testing	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.
Illumina Laboratory Services, Illumina	RCV001160121	SCV001321891	uncertain significance	CFTR-related disorders	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Mayo Clinic Laboratories, Mayo Clinic	RCV000587447	SCV001715965	uncertain significance	not provided	2022-10-26	criteria provided, single submitter	clinical testing	PM2, PM3_strong
Johns Hopkins Genomics, Johns Hopkins University	RCV000206091	SCV001905480	likely pathogenic	Cystic fibrosis	2021-08-24	criteria provided, single submitter	clinical testing	CFTR variant associated with varying clinical consequence. See www.CFTR2.org for phenotype information.
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000587447	SCV002009132	uncertain significance	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV000206091	SCV002507363	uncertain significance	Cystic fibrosis	2019-07-29	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV001762431	SCV002529708	uncertain significance	Hereditary pancreatitis	2022-02-09	criteria provided, single submitter	curation
MGZ Medical Genetics Center	RCV000206091	SCV002580890	likely pathogenic	Cystic fibrosis	2022-08-30	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000587447	SCV004160966	uncertain significance	not provided	2022-04-01	criteria provided, single submitter	clinical testing	CFTR: PM3, PM2:Supporting, PS3:Supporting, PS4:Supporting
Baylor Genetics	RCV003468932	SCV004215209	uncertain significance	Bronchiectasis with or without elevated sweat chloride 1	2023-01-22	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003947666	SCV004765301	uncertain significance	CFTR-related condition	2023-12-28	criteria provided, single submitter	clinical testing	The CFTR c.2900T>C variant is predicted to result in the amino acid substitution p.Leu967Ser. This variant has been reported in the compound heterozygous state in individuals with hypertrypsinemia (Boyne et al. 2000. PubMed ID: 10970190) and acute recurrent pancreatitis (Lucidi et al. 2011. PubMed ID: 21499205). This variant in the compound heterozygous or heterozygous state has also been found in individuals with chronic pancreatitis (see for example Steiner et al. 2011. PubMed ID: 21520337; Masson et al. 2013. PubMed ID: 23951356; LaRusch et al. 2014. PubMed ID: 25033378) as well as individuals with suspected cystic fibrosis (see for example Schrijver et al. 2005. PubMed ID: 15858154; Ziętkiewicz et al. 2014. PubMed ID: 24586523). However, this variant has also been reported not to be causative for cystic fibrosis (Wang et al. 2000. PubMed ID: 11025834). Functional studies showed that this variant possesses ~74.4% of wildtype CFTR activity (Raraigh et al. 2018. PubMed ID: 29805046). This variant is reported in 0.13% of alleles in individuals of Latino descent in gnomAD and has conflicting interpretations of pathogenicity in ClinVar ranging from uncertain to pathogenic (http://www.ncbi.nlm.nih.gov/clinvar/variation/219537). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
MAGI's Lab - Research, MAGI Group	RCV001327945	SCV001432723	uncertain significance	Infertility disorder		no assertion criteria provided	provider interpretation
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000587447	SCV001951065	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000587447	SCV001972039	uncertain significance	not provided		no assertion criteria provided	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000587447	SCV001978707	uncertain significance	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV001160121	SCV002507447	uncertain significance	CFTR-related disorders	2019-07-29	no assertion criteria provided	clinical testing