Total submissions: 29
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Department of Pathology and Laboratory Medicine, |
RCV000206091 | SCV005918432 | uncertain significance | Cystic fibrosis | 2023-06-28 | criteria provided, single submitter | research | |
| Greenwood Genetic Center Diagnostic Laboratories, |
RCV000587447 | SCV005873947 | uncertain significance | not provided | 2024-09-11 | criteria provided, single submitter | clinical testing | PM2, PP3 |
| Fulgent Genetics, |
RCV005031775 | SCV005666388 | uncertain significance | Bronchiectasis with or without elevated sweat chloride 1; Cystic fibrosis; Hereditary pancreatitis; Congenital bilateral aplasia of vas deferens from CFTR mutation | 2024-06-10 | criteria provided, single submitter | clinical testing | |
| Clinical Genomics Laboratory, |
RCV000206091 | SCV005045060 | uncertain significance | Cystic fibrosis | 2023-11-14 | criteria provided, single submitter | clinical testing | 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. |
| North West Genomic Laboratory Hub, |
RCV000206091 | SCV004814228 | likely pathogenic | Cystic fibrosis | 2020-07-31 | criteria provided, single submitter | clinical testing | Criteria Codes: PM3_VStr PM2 |
| Baylor Genetics | RCV003468932 | SCV004215209 | uncertain significance | Bronchiectasis with or without elevated sweat chloride 1 | 2023-01-22 | criteria provided, single submitter | clinical testing | |
| Ce |
RCV000587447 | SCV004160966 | uncertain significance | not provided | 2022-04-01 | criteria provided, single submitter | clinical testing | CFTR: PM3, PM2:Supporting, PS3:Supporting, PS4:Supporting |
| MGZ Medical Genetics Center | RCV000206091 | SCV002580890 | likely pathogenic | Cystic fibrosis | 2022-08-30 | criteria provided, single submitter | clinical testing | |
| Sema4, |
RCV001762431 | SCV002529708 | uncertain significance | Hereditary pancreatitis | 2022-02-09 | criteria provided, single submitter | curation | |
| Genome Diagnostics Laboratory, |
RCV000206091 | SCV002507363 | uncertain significance | Cystic fibrosis | 2019-07-29 | criteria provided, single submitter | clinical testing | |
| Institute for Clinical Genetics, |
RCV000587447 | SCV002009132 | uncertain significance | not provided | 2021-11-03 | criteria provided, single submitter | clinical testing | |
| Johns Hopkins Genomics, |
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. |
| Mayo Clinic Laboratories, |
RCV000587447 | SCV001715965 | uncertain significance | not provided | 2022-10-26 | criteria provided, single submitter | clinical testing | PM2, PM3_strong |
| Illumina Laboratory Services, |
RCV001160121 | SCV001321891 | uncertain significance | CFTR-related disorder | 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. |
| Ambry Genetics | RCV000206091 | SCV001177923 | uncertain significance | Cystic fibrosis | 2024-12-11 | 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 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 significantly alters bicarbonate permeability and conductance (LaRusch J et al. PLoS Genet., 2014 Jul;10:e1004376). Other functional studies showed reduced CFTR function; however, the clinical relevance of this finding is unclear (Raraigh KS et al. Am. J. Hum. Genet., 2018 Jun;102:1062-1077; Bihler H et al. J Cyst Fibros, 2024 Jul;23:664-675). The variant has been reported as non CF-causing (The Clinical and Functional TRanslation of CFTR (CFTR2); available at http://cftr2.org. Accessed December 11, 2024). Based on data from gnomAD, the frequency for this variant is above the maximum credible frequency for a disease-causing variant in this gene based on internally established thresholds (Karczewski et al. Nature. 2020 May;581(7809):434-443; Whiffin et al. Genet Med. 2017 10;19:1151-1158). 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, this variant is unlikely to be causative of classic cystic fibrosis; however, its contribution to the development of a CFTR-related disorder is uncertain. This alteration is thus classified as a variant of unknown significance. |
| Quest Diagnostics Nichols Institute San Juan Capistrano | RCV000587447 | SCV000889303 | uncertain significance | not provided | 2024-05-06 | criteria provided, single submitter | clinical testing | The CFTR c.2900T>C (p.Leu967Ser) variant has been reported in the published literature in a heterozygous state in individuals with pancreatitis (PMID: 21520337 (2011), 23951356 (2013)). It has also been reported in a compound heterozygous state with other CFTR pathogenic variants in individuals with pancreatitis (PMID: 23951356 (2013)), bronchitis (PMID: 25033378 (2014)), asthma, allergic bronchopulmonary aspergillosis (ABPA) (PMID: 33768849 (2021)), and other unspecified CF-like symptoms (PMID: 27214204 (2016)). Experimental evidence regarding the effect of this variant on protein function is conflicting (PMID: 25033378 (2014), 29805046 (2018)). The frequency of this variant in the general population, 0.0016 (82/50762 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. |
| Mendelics | RCV000206091 | SCV000886148 | likely pathogenic | Cystic fibrosis | 2018-11-05 | criteria provided, single submitter | clinical testing | |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV000664323 | SCV000696932 | uncertain significance | not specified | 2025-03-25 | 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. This frequency is not significantly higher than estimated 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). Other studies indicated that L967S maintained 74-79% of wild-type function (Raraigh_2018, BIhler_2024). The following publications have been ascertained in the context of this evaluation (PMID: 31088717, 11938439, 38388235, 16193325, 32784480, 33768849, 7691344, 16134171, 18195584, 29589582, 12167682, 25033378, 21499205, 24451227, 23951356, 33946859, 25963003, 29805046, 38871151, 25824995, 15858154, 28544683, 21520337, 11025834, 24586523, 21184098). ClinVar contains an entry for this variant (Variation ID: 219537). Based on the evidence outlined above, the variant was classified as uncertain significance. |
| ARUP Laboratories, |
RCV005031775 | SCV000603067 | pathogenic | Bronchiectasis with or without elevated sweat chloride 1; Cystic fibrosis; Hereditary pancreatitis; Congenital bilateral aplasia of vas deferens from CFTR mutation | 2024-08-07 | 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. 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. PMID: 16193325 Cohn JA et al. Increased risk of idiopathic chronic pancreatitis in cystic fibrosis carriers. Hum Mutat. 2005 Oct;26(4):303-7. PMID: 16134171 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 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 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. PMID: 29805046 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. PMID: 11025834 |
| Gene |
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. |
| Eurofins Ntd Llc |
RCV000587447 | SCV000331169 | uncertain significance | not provided | 2018-08-23 | criteria provided, single submitter | clinical testing | |
| Labcorp Genetics |
RCV000206091 | SCV000259453 | uncertain significance | Cystic fibrosis | 2025-02-01 | 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 CFTR-related conditions (PMID: 16134171, 23951356, 25033378, 33768849). ClinVar contains an entry for this variant (Variation ID: 219537). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt CFTR protein function with a negative predictive value of 80%. 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. |
| Prevention |
RCV001160121 | SCV004765301 | uncertain significance | CFTR-related disorder | 2023-12-28 | no assertion criteria provided | 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. |
| Genome Diagnostics Laboratory, |
RCV001160121 | SCV002507447 | uncertain significance | CFTR-related disorder | 2019-07-29 | no assertion criteria provided | clinical testing | |
| Diagnostic Laboratory, |
RCV000587447 | SCV001978707 | uncertain significance | not provided | no assertion criteria provided | clinical testing | ||
| Clinical Genetics DNA and cytogenetics Diagnostics Lab, |
RCV000587447 | SCV001972039 | uncertain significance | not provided | no assertion criteria provided | clinical testing | ||
| Joint Genome Diagnostic Labs from Nijmegen and Maastricht, |
RCV000587447 | SCV001951065 | uncertain significance | not provided | no assertion criteria provided | clinical testing | ||
| MAGI's Lab - |
RCV001327945 | SCV001432723 | uncertain significance | Infertility disorder | no assertion criteria provided | provider interpretation | ||
| Counsyl | RCV000206091 | SCV000796460 | uncertain significance | Cystic fibrosis | 2017-12-14 | no assertion criteria provided | clinical testing | This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. |