rs1800110
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Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 5P and 1B. PM1PM2PP5BP4
The ENST00000003084.11(CFTR):c.2900T>C(p.Leu967Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00135 in 1,613,804 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. L967L) has been classified as Likely benign.
Frequency
Genomes: 𝑓 0.0010 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0014 ( 1 hom. )
Consequence
CFTR
ENST00000003084.11 missense
ENST00000003084.11 missense
Scores
3
10
6
Clinical Significance
Conservation
PhyloP100: 4.04
Genes affected
CFTR (HGNC:1884): (CF transmembrane conductance regulator) This gene encodes a member of the ATP-binding cassette (ABC) transporter superfamily. The encoded protein functions as a chloride channel, making it unique among members of this protein family, and controls ion and water secretion and absorption in epithelial tissues. Channel activation is mediated by cycles of regulatory domain phosphorylation, ATP-binding by the nucleotide-binding domains, and ATP hydrolysis. Mutations in this gene cause cystic fibrosis, the most common lethal genetic disorder in populations of Northern European descent. The most frequently occurring mutation in cystic fibrosis, DeltaF508, results in impaired folding and trafficking of the encoded protein. Multiple pseudogenes have been identified in the human genome. [provided by RefSeq, Aug 2017]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 4 ACMG points.
PM1
In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 11 uncertain in ENST00000003084.11
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 7-117603774-T-C is Pathogenic according to our data. Variant chr7-117603774-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 219537.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=4, Pathogenic=1, Uncertain_significance=15}. Variant chr7-117603774-T-C is described in Lovd as [Likely_pathogenic].
BP4
Computational evidence support a benign effect (MetaRNN=0.13665617). . Strength limited to SUPPORTING due to the PP5.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| CFTR | NM_000492.4 | c.2900T>C | p.Leu967Ser | missense_variant | 17/27 | ENST00000003084.11 | NP_000483.3 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| CFTR | ENST00000003084.11 | c.2900T>C | p.Leu967Ser | missense_variant | 17/27 | 1 | NM_000492.4 | ENSP00000003084 | P2 |
Frequencies
GnomAD3 genomes 0.00104 AC: 158AN: 152190Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.000721 AC: 181AN: 251214Hom.: 0 AF XY: 0.000641 AC XY: 87AN XY: 135790
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GnomAD4 exome AF: 0.00138 AC: 2022AN: 1461496Hom.: 1 Cov.: 32 AF XY: 0.00134 AC XY: 974AN XY: 727054
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GnomAD4 genome 0.00104 AC: 158AN: 152308Hom.: 0 Cov.: 33 AF XY: 0.00103 AC XY: 77AN XY: 74498
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:5Uncertain:21
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Pathogenic:1Uncertain:9
| Uncertain significance, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden | Nov 03, 2021 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Apr 01, 2022 | CFTR: PM3, PM2:Supporting, PS3:Supporting, PS4:Supporting - |
| Uncertain significance, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Aug 23, 2018 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Oct 26, 2022 | PM2, PM3_strong - |
| Uncertain significance, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | May 05, 2023 | 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)). - |
| Pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Jul 27, 2020 | 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. - |
| Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jun 14, 2017 | 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. - |
Cystic fibrosis Pathogenic:4Uncertain:5
| Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 23, 2023 | 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. - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Oct 28, 2022 | 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. - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Dec 14, 2017 | - - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Johns Hopkins Genomics, Johns Hopkins University | Aug 24, 2021 | CFTR variant associated with varying clinical consequence. See www.CFTR2.org for phenotype information. - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Genome Diagnostics Laboratory, The Hospital for Sick Children | Jul 29, 2019 | - - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | MGZ Medical Genetics Center | Aug 30, 2022 | - - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Mendelics | Nov 05, 2018 | - - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | North West Genomic Laboratory Hub, Manchester University NHS Foundation Trust | Jul 31, 2020 | Criteria Codes: PM3_VStr PM2 - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Clinical Genomics Laboratory, Washington University in St. Louis | Nov 14, 2023 | 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. - |
CFTR-related disorder Uncertain:3
| Uncertain significance, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, The Hospital for Sick Children | Jul 29, 2019 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | 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. - |
| Uncertain significance, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Dec 28, 2023 | 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. - |
not specified Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Sep 20, 2024 | 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. Four of four 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, 34996830, 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. - |
Infertility disorder Uncertain:1
| Uncertain significance, no assertion criteria provided | provider interpretation | MAGI's Lab - Research, MAGI Group | - | - - |
Hereditary pancreatitis Uncertain:1
| Uncertain significance, criteria provided, single submitter | curation | Sema4, Sema4 | Feb 09, 2022 | - - |
Bronchiectasis with or without elevated sweat chloride 1 Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Jan 22, 2023 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Uncertain
T
BayesDel_noAF
Pathogenic
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Uncertain
T;.;.;T;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D;D;D;D
M_CAP
Uncertain
D
MetaRNN
Benign
T;T;T;T;T
MetaSVM
Uncertain
D
MutationAssessor
Benign
L;.;.;.;.
MutationTaster
Benign
D;D
PrimateAI
Benign
T
PROVEAN
Benign
N;.;.;N;.
REVEL
Pathogenic
Sift
Uncertain
D;.;.;D;.
Sift4G
Pathogenic
D;.;.;D;.
Polyphen
D;.;.;.;.
Vest4
MVP
MPC
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
Name
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at