rs200321110
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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.3205G>A(p.Gly1069Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000136 in 1,613,472 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.00024 ( 0 hom., cov: 31)
Exomes 𝑓: 0.00013 ( 0 hom. )
Consequence
CFTR
ENST00000003084.11 missense
ENST00000003084.11 missense
Scores
3
7
9
Clinical Significance
Conservation
PhyloP100: 6.85
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 9 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 uncertain in ENST00000003084.11
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 7-117611646-G-A is Pathogenic according to our data. Variant chr7-117611646-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 53684.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=6, Pathogenic=2, Uncertain_significance=7}. Variant chr7-117611646-G-A is described in Lovd as [Pathogenic].
BP4
Computational evidence support a benign effect (MetaRNN=0.24175769). . 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.3205G>A | p.Gly1069Arg | missense_variant | 20/27 | ENST00000003084.11 | NP_000483.3 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| CFTR | ENST00000003084.11 | c.3205G>A | p.Gly1069Arg | missense_variant | 20/27 | 1 | NM_000492.4 | ENSP00000003084 | P2 | |
| ENST00000456270.1 | n.177+4583C>T | intron_variant, non_coding_transcript_variant | 3 |
Frequencies
GnomAD3 genomes 0.000243 AC: 37AN: 151976Hom.: 0 Cov.: 31
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GnomAD3 exomes AF: 0.000255 AC: 64AN: 250934Hom.: 0 AF XY: 0.000206 AC XY: 28AN XY: 135626
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GnomAD4 exome AF: 0.000125 AC: 183AN: 1461378Hom.: 0 Cov.: 31 AF XY: 0.000129 AC XY: 94AN XY: 726980
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GnomAD4 genome 0.000243 AC: 37AN: 152094Hom.: 0 Cov.: 31 AF XY: 0.000282 AC XY: 21AN XY: 74348
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:11Uncertain:8
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Cystic fibrosis Pathogenic:4Uncertain:3
| Likely pathogenic, no assertion criteria provided | clinical testing | Baylor Genetics | Feb 21, 2022 | - - |
| Likely pathogenic, criteria provided, single submitter | curation | Laboratory of Medical Genetics, National & Kapodistrian University of Athens | Feb 01, 2024 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Genome Diagnostics Laboratory, The Hospital for Sick Children | Jul 30, 2020 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Nov 22, 2017 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Sep 27, 2022 | This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 1069 of the CFTR protein (p.Gly1069Arg). This variant is present in population databases (rs200321110, gnomAD 0.1%). This missense change has been observed in individual(s) with cystic fibrosis, congenital bilateral absence of the vas deferens, and chronic pancreatitis (PMID: 8528204, 9239681, 11729110, 17003641, 17329263, 20460946, 23951356, 23974870, 25033378, 25869325, 25910067). ClinVar contains an entry for this variant (Variation ID: 53684). 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: 8662892, 18305154). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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. - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Johns Hopkins Genomics, Johns Hopkins University | Feb 10, 2020 | CFTR variant associated with variable clinical consequences. See www.CFTR2.org for phenotype information. - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 26, 2024 | The p.G1069R variant (also known as c.3205G>A), located in coding exon 20 of the CFTR gene, results from a G to A substitution at nucleotide position 3205. The glycine at codon 1069 is replaced by arginine, an amino acid with dissimilar properties. This variant was first reported in an individual with cystic fibrosis, pancreatic insufficiency, and significant lung disease in cis with a nonsense mutation and in trans with p.F508del (Savov A et al. Hum. Mol. Genet., 1994 Jan;3:57-60). The p.G1069R variant has been reported as a variant of varying clinical consequences (VVCC) and has been identified in trans with a pathogenic mutation in individuals with intermediate sweat chloride levels and pancreatic insufficiency (Sosnay PR et al. Nat. Genet. 2013 Oct; 45(10):1160-7; Sosnay PR et al. Pediatr. Clin. North Am., 2016 08;63:585-98). Two siblings with idiopathic chronic pancreatitis (ICP) were both found to be heterozygous for p.G1069R and a second variant in CFTR; however, phase was not confirmed (Noone PG et al. Gastroenterology, 2001 Dec;121:1310-9). Another study of individuals with ICP identified this variant in an individual who was also heterozygous for the p.N34S mutation in SPINK1 (Masson E et al. PLoS ONE, 2013 Aug;8:e73522). Functional studies demonstrated that while the p.G1069R variant in CFTR does not impact protein maturation or conductance, it does reduce the probability of channel opening (Seibert FS et al. J. Biol. Chem., 1996 Jun;271:15139-45). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the majority of available evidence to date, this variant is likely to be pathogenic. - |
CFTR-related disorder Pathogenic:3Uncertain:2
| Likely pathogenic, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, The Hospital for Sick Children | Jul 30, 2020 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 28, 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). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. - |
| Likely pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | May 20, 2019 | - - |
| Uncertain significance, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Aug 21, 2024 | The CFTR c.3205G>A variant is predicted to result in the amino acid substitution p.Gly1069Arg. This variant has been reported for a range of phenotypes including pancreatitis, bronchiectasis, sarcoidosis, cystic fibrosis and congenital bilateral absence of the vas deferens (Masson et al 2013. PubMed ID: 23951356; Keiles et al 2006. PubMed ID: 17003641; Ratbi et al 2007. PubMed ID: 17329263; Bombieri et al 2000. PubMed ID: 10980579; Guan et al 2018. PubMed ID: 29997923). Functional studies in cell lines suggest the p.Gly1069Arg variant does not affect CFTR transmembrane conductance (see supplemental table 2 in Sosnay et al 2013. PubMed ID: 23974870; Seibert et al 1996. PubMed ID: 8662892). This variant has conflicting interpretations in ClinVar ranging from uncertain significance to pathogenic by different laboratories (https://www.ncbi.nlm.nih.gov/clinvar/variation/53684/). This variant is reported in 0.12% of alleles in individuals of East Asian descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
| Pathogenic, criteria provided, single submitter | curation | CFTR-France | Jul 03, 2015 | - - |
not provided Pathogenic:2Uncertain:1
| Likely pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Jun 30, 2017 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Apr 12, 2016 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Nov 08, 2022 | The CFTR c.3205G>A; p.Gly1069Arg variant (rs200321110) is reported in the literature in multiple individuals affected with CFTR-related disorders (Keiles 2006, LaRusch 2014, Masson 2013, Ratbi 2007). It has also been reported in patients with cystic fibrosis without an identified second variant in CFTR (Angelicheva 1997, Savov 1994, Sosnay 2013), and was found in-cis with a truncating variant in one patient (Savov 1994). This variant is reported in ClinVar (Variation ID: 53684), and is found in the general population with an overall allele frequency of 0.027% (75/282294 alleles) in the Genome Aggregation Database. The glycine at codon 1069 is moderately conserved, and computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.603). However, other computational analyses (Alamut v.2.11) predict that this variant may impact splicing by creating a novel cryptic acceptor splice site. In vitro functional analyses demonstrate that this variant does not alter protein expression, but reduces channel function (Seibert 1996). Based on the range of clinical symptoms observed in patients with this variant, we consider the p.Gly1069Arg variant to be pathogenic with varying clinical consequences. References: Angelicheva D et al. Cystic fibrosis mutations and associated haplotypes in Bulgaria - a comparative population genetic study. Hum Genet. 1997 Apr;99(4):513-20. PMID: 9099843. Guan WJ et al. Next-generation sequencing for identifying genetic mutations in adults with bronchiectasis. J Thorac Dis. 2018 May;10(5):2618-2630. PMID: 29997923. Keiles S and Kammesheidt A. Identification of CFTR, PRSS1, and SPINK1 mutations in 381 patients with pancreatitis. Pancreas. 2006 Oct;33(3):221-7. PMID: 17003641. 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 Jul 17;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 Aug 8;8(8):e73522. PMID: 23951356. Ratbi I et al. Detection of cystic fibrosis transmembrane conductance regulator (CFTR) gene rearrangements enriches the mutation spectrum in congenital bilateral absence of the vas deferens and impacts on genetic counselling. Hum Reprod. 2007 May;22(5):1285-91. PMID: 17329263. Savov A et al. Identification of six novel mutations in the CFTR gene of patients from Bulgaria by screening the twenty seven exons and exon/intron boundaries using DGGE and direct DNA sequencing. Hum Mol Genet. 1994 Jan;3(1):57-60. PMID: 7512860. Seibert FS et al. Disease-associated mutations in the fourth cytoplasmic loop of cystic fibrosis transmembrane conductance regulator compromise biosynthetic processing and chloride channel activity. J Biol Chem. 1996 Jun 21;271(25):15139-45. PMID: 8662892. Sosnay PR et al. Defining the disease liability of variants in the cystic fibrosis transmembrane conductance regulator gene. Nat Genet. 2013 Oct;45(10):1160-7. PMID: 23974870. Zou WB et al. SPINK1, PRSS1, CTRC, and CFTR Genotypes Influence Disease Onset and Clinical Outcomes in Chronic Pancreatitis. Clin Transl Gastroenterol. 2018 Nov 12;9(11):204. PMID: 30420730. - |
Cystic fibrosis;C0403814:Congenital bilateral aplasia of vas deferens from CFTR mutation Pathogenic:1
| Likely pathogenic, criteria provided, single submitter | clinical testing | Juno Genomics, Hangzhou Juno Genomics, Inc | - | PM3_Strong+PP4+PS3_Supporting - |
Bronchiectasis with or without elevated sweat chloride 1 Pathogenic:1
| Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 30, 2024 | - - |
not specified Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Sep 24, 2024 | Variant summary: CFTR c.3205G>A (p.Gly1069Arg) results in a non-conservative amino acid change located in the ABC transporter type 1, transmembrane domain (IPR011527) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00026 in 251634 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in CFTR causing CFTR-Related Diseases (0.00026 vs 0.013), allowing no conclusion about variant significance. c.3205G>A has been reported in the literature in compound heterozygosity with a second pathogenic CFTR mutation in individuals affected with CF (e.g. DeBoeck_2005, Savov_1995, Mota_2018, Petrova_2019) and chronic pancreatitis (e.g. Keiles_2006, Noone_2001), but also in an infant reported with a positive immunoreactive trypsinogen test upon newborn screening whom did not exhibit other signs or symptoms of CF or CF-related disease upon follow-ups through the age of 3 years (Ooi_2015). The variant has also been reported in multiple individuals affected with these and other CFTR-Related Diseases, including pancreatitis, congenital bilateral absence of the vas deferens , and classical CF, but without a second CFTR mutation identified/specified (e.g. Chang_2007, Faucz_2007, Giefer_2017, Lucarelli_2015, Ooi_2015, Sofia_2016, Soltysova_2017, Sosnay_2013, Petrova_2019, Luo_2021, Raraigh_2022), therefore these data do not allow any definitive conclusions about variant significance. In addition, the variant has been reported in phase with another pathogenic mutation in several affected individuals, including at least 4 occurrences in cis with p.Leu88X in CF patients from Bulgaria and Greece (e.g. Ratbi_2007), and at least 2 occurrences in cis with p.Tyr109Cys in CF patients from Brazil (e.g. Mota_2018), suggesting that the phenotype in these individuals may not be attributable to the p.Gly1069Arg variant. Furthermore, co-occurrence with another pathogenic variant associated with pancreatitis risk has also been reported in an individual affected with chronic pancreatitis (SPINK1, p.Asn34Ser; Masson_2013), therefore the contributions of the individual variants to the phenotype in this patient cannot be determined. Several publications report in vitro experimental evidence suggesting that the variant does not affect protein expression or maturation, but may alter intracellular localization and moderately impair channel function (e.g. Dong_2012, Seiber_1996, Serohijos_2008). The following publications have been ascertained in the context of this evaluation (PMID: 10980579, 17539902, 10923036, 15772171, 22210114, 17718859, 28502372, 29589582, 29997923, 17003641, 25910067, 32777524, 23951356, 30232781, 11729110, 25963003, 31245908, 34782259, 17329263, 8528204, 8662892, 18305154, 27264265, 28544683, 23974870, 32150665). ClinVar contains an entry for this variant (Variation ID: 53684). The CFTR2 database cites this variant as having varying consequences, indicating that some patients with this variant, combined with another CF-causing variant, have CF while others do not, suggesting that clinical information is necessary for diagnosis of disease in individuals found to carry this variant. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic until additional information becomes available. - |
Hereditary pancreatitis Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Apr 05, 2022 | Criteria applied: PM3, PP3 this Variant was identiefied with NM_003122.5 (SPINK1):c.101A>G, p.(Asn34Ser) and the UTR variant c.-4141G>T in patient with hereditary pancreatitis - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Uncertain
CADD
Uncertain
DANN
Benign
DEOGEN2
Uncertain
T;.;.;T;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D;D;D;D
M_CAP
Pathogenic
D
MetaRNN
Benign
T;T;T;T;T
MetaSVM
Uncertain
T
MutationAssessor
Benign
L;.;.;.;.
MutationTaster
Benign
D;D
PrimateAI
Pathogenic
D
PROVEAN
Benign
N;.;.;N;.
REVEL
Uncertain
Sift
Benign
T;.;.;T;.
Sift4G
Benign
T;.;.;T;.
Polyphen
P;.;.;.;.
Vest4
MutPred
Gain of MoRF binding (P = 0.025);.;.;.;.;
MVP
MPC
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
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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