ClinVar Miner

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

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000206091 SCV000259453 uncertain significance Cystic fibrosis 2019-12-22 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 RCV000664323 SCV000603067 pathogenic not specified 2018-07-20 criteria provided, single submitter clinical testing The CFTR c.2900T>C, p.Leu967Ser variant is reported in multiple individuals with transient hypertrypsinaemia (Boyne 2000) or chronic pancreatitis (Masson 2013, Steiner 2011). It is observed at a higher frequency in individuals diagnosed with pancreatitis than unaffected individuals (odds ratio >5, p<0.05) (LaRusch 2014). The variant was found in trans with the pathogenic variant p.Phe508del in a patient with chronic pancreatitis, but other clinical symptoms were not provided (Masson 2013). 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 (Mutation Taster, PolyPhen, SIFT) predict this variant is deleterious. Functional assays suggest this variant has a modest effect or no effect on chloride channel activity but exhibits decreased bicarbonate transport (LaRusch 2014, Raraigh 2018). While it is not known to be associated with classic cystic fibrosis, based on available information, this variant is classified as mildly pathogenic for pancreatitis. References: Boyne J et al. Many deltaF508 heterozygote neonates with transient hypertrypsinaemia have a second, mild CFTR mutation. J Med Genet. 2000 37(7):543-7. 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. Steiner B et al. Common CFTR haplotypes and susceptibility to chronic pancreatitis and congenital bilateral absence of the vas deferens. Hum Mutat. 2011 32(8):912-20.
Integrated Genetics/Laboratory Corporation of America RCV000587447 SCV000696932 uncertain significance not provided 2017-05-11 criteria provided, single submitter clinical testing Variant summary: The CFTR c.2900T>C (p.Leu967Ser) variant involves the alteration of a conserved nucleotide, resulting in a missense substitution that lies within the ABC transporter type 1, transmembrane domain (InterPro). 5/5 in silico tools predict a damaging outcome for this variant. This variant was found in the large control database ExAC at a frequency of 0.0005638 (71/125928 control chromosomes), which does not exceed the estimated maximal expected allele frequency of a pathogenic CFTR variant (0.0129603). In the literature, the variant has been cited in at least one CF and one CBAVD patients, several other patients with non-classic CF and pancreatitis, and in a fetus with bowel anomalies. Patients with pacreatitis were also found to carry another CFTR variant or another variant 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 CFTR gene in two patients who had compound heterozygous genotype p.Phe508del/c.3191_3192ins16 (de Becdelivre_2011) and c.489+2T>G/p.Arg792X), suggesting that L967S was not causative in those patients and is unlikely to be pathogenic in the autosomal recessive Mendelian inheritance pattern. In contrast, case-control studies (LaRusch_2014 and Steiner_2011) suggest that L967S may increase the risk of developing pancreatitis (Odds ratio=7.59, CI: 1.68 to 34.30). In vitro functional studies of L967S show that it has normal chloride but not bicarbonate permeability and conductance with WNK1-SPAK activation (LaRusch_PLOS Genetics_2014). Multiple clinical diagnostic laboratories/reputable databases have classified this variant as uncertain significance. Taken together, this variant is classified as VUS until more definitive data becomes available.
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 Insufficient evidence
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.

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