ClinVar Miner

Submissions for variant NM_000492.4(CFTR):c.2900T>C (p.Leu967Ser) (rs1800110)

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Total submissions: 14
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000206091 SCV000259453 uncertain significance Cystic fibrosis 2020-10-27 criteria provided, single submitter clinical testing This sequence change replaces leucine with serine at codon 967 of the CFTR protein (p.Leu967Ser). The leucine residue is moderately conserved and there is a large physicochemical difference between leucine and serine. This variant is present in population databases (rs1800110, ExAC 0.1%). This variant has been reported in individuals with idiopathic chronic pancreatitis (PMID: 21520337, 23951356, 25033378, 16193325, 16134171) or with suspected cystic fibrosis (PMID: 12167682, 15858154, 24586523), although it is not always clear whether these individuals carried any additional CFTR variants. It has also been observed as compound heterozygous with a pathogenic mutation in CFTR gene in an infant with hypertrypsinemia, and in a child with acute recurrent pancreatitis but without any indication in both cases of lung disease (PMID: 10970190, 21499205), which suggests the that this p.Leu967Ser substitution is not a primary cause of cystic fibrosis. This variant is also known as c.3032T>C in the literature. ClinVar contains an entry for this variant (Variation ID: 219537). An experimental study has shown that this missense change does not affect CFTR expression, stability, or chloride conductance, but has a mild effect on bicarbonate conductance in cell culture (PMID: 25033378). 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.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics 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 RCV001283535 SCV000603067 pathogenic none 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 2021-04-05 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 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. Ten other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (Uncertain significance, n=7; Likely Pathogenic, n=1; Pathogenic, n=2). 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 2019-08-13 criteria provided, single submitter clinical testing
Ambry Genetics RCV001016917 SCV001177923 uncertain significance Inborn genetic diseases 2018-12-18 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). <span style="background-color:initial">Several studies have reported this alteration in individuals with pancreatitis, some with additional alterations in SPINK1 and/or <span style="background-color:initial">CFTR <span style="background-color:initial">(Audrezet MP et al. Eur J Hum Genet<span style="background-color:initial">. 2002;10(2):100-106; Cohn JA et al. Hum Mutat<span style="background-color:initial">. 2005;26(4):303-307; Bishop MD et al. Hum Genet<span style="background-color:initial">. 2005;118(3-4):372-381; <span style="background-color:initial">Masson et al. PLoS ONE <span style="background-color:initial">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 Clinical Services Laboratory,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 2020-02-21 criteria provided, single submitter clinical testing
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.
MAGI's Lab - Research,MAGI Group RCV001327945 SCV001432723 uncertain significance Infertility no assertion criteria provided provider interpretation
Human Genetics - Radboudumc,Radboudumc RCV000587447 SCV001951065 uncertain significance not provided no assertion criteria provided clinical testing

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