ClinVar Miner

Submissions for variant NM_000492.4(CFTR):c.890G>A (p.Arg297Gln) (rs143486492)

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Total submissions: 13
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000987959 SCV000075295 benign Cystic fibrosis 2020-12-05 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000180169 SCV000232561 likely benign not specified 2014-09-26 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001282191 SCV000602982 uncertain significance none provided 2019-08-10 criteria provided, single submitter clinical testing The CFTR c.890G>A; p.Arg297Gln variant (rs143486492) is reported in the literature in multiple individuals affected with CFTR-related disorders (Casals 2004, Gallati 2009, Keiles 2006, Masson 2013, Sultan 2012). However, this variant has also been reported on the same chromosome as the 5T variant in IVS 8 (Hughes 2001, Tzetis 2001), and did not segregate with disease in at least one family (Dorval 1995). This variant is reported in ClinVar (Variation ID: 54082), and is found in the non-Finnish European population with an allele frequency of 0.12% (153/128492 alleles) in the Genome Aggregation Database. The arginine at codon 297 is highly conserved, and computational analyses (SIFT: damaging, PolyPhen-2: benign) predict conflicting effects of this variant on protein structure/function. Functional analyses of the variant protein show normal chloride channel activity (Chen 2000, Seibert 1997), but a defect in bicarbonate transport (Choi 2001). Due to conflicting information, the clinical significance of the p.Arg297Gln variant is uncertain at this time. References: Casals T et al. Different CFTR mutational spectrum in alcoholic and idiopathic chronic pancreatitis? Pancreas. 2004 28(4):374-9. Chen EY et al. Cystic fibrosis transmembrane conductance regulator has an altered structure when its maturation is inhibited. Biochemistry. 2000 Apr 4;39(13):3797-803. Choi JY et al. Aberrant CFTR-dependent HCO3- transport in mutations associated with cystic fibrosis. Nature. 2001 Mar 1;410(6824):94-7. Dorval I et al. French CF family genotype analysis shows that the R297Q mutation is a rare polymorphism. Hum Mutat. 1995;6(4):334-5. Gallati S et al. Cystic fibrosis transmembrane conductance regulator mutations in azoospermic and oligospermic men and their partners. Reprod Biomed Online. 2009 19(5):685-94. Hughes D et al. Mutation and haplotype analysis of the CFTR gene in atypically mild cystic fibrosis patients from Northern Ireland. J Med Genet. 2001 Feb;38(2):136-9. Keiles S et al. Identification of CFTR, PRSS1, and SPINK1 mutations in 381 patients with pancreatitis. Pancreas. 2006 33(3):221-7. 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. Seibert FS et al. Disease-associated mutations in cytoplasmic loops 1 and 2 of cystic fibrosis transmembrane conductance regulator impede processing or opening of the channel. Biochemistry. 1997 Sep 30;36(39):11966-74. Sultan M et al. Genetic prevalence and characteristics in children with recurrent pancreatitis. J Pediatr Gastroenterol Nutr. 2012 54(5):645-50. Tzetis M et al. CFTR gene mutations--including three novel nucleotide substitutions--and haplotype background in patients with asthma, disseminated bronchiectasis and chronic obstructive pulmonary disease. Hum Genet. 2001 108(3):216-21.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000180169 SCV000697053 likely benign not specified 2020-09-24 criteria provided, single submitter clinical testing Variant summary: CFTR c.890G>A (p.Arg297Gln) results in a conservative amino acid change located in the first transmembrane domain (IPR011527), within the second cytoplasmic loop (Choi 2001) 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 0.00063 in 281950 control chromosomes, predominantly at a frequency of 0.0012 within the Non-Finnish European subpopulation in the gnomAD database. This frequency is lower than the expected maximum for a pathogenic variant in CFTR causing Cystic Fibrosis (0.00064 vs 0.013), allowing no conclusion about variant significance. c.890G>A has been reported in the literature in multiple individuals affected with a milder, atypical form of cystic fibrosis (Graham 1991,Hughes 2001) and was detected during newborn screening in neonates with positive sweat test results (Scotet 2000), however in this later study the CFTR gene was not fully sequenced. The variant was also reported with various CFTR-related phenotypes, e.g. asthma (Tzetis 2001) and infertility (Ravnik-Glavac 2001, Gallati 2009). However, multiple affected individuals were reported to carry another pathogenic CFTR variant in cis with the variant of interest (Graham 1991, Hughes 2001, Tzetis 2001), along with a family study indicating that the variant did not segregate with the disease (Dorval 1995). The variant was also reported in patients affected with chronic or recurrent pancreatitis (e.g. Casals 2004, Keiles 2006, Sutton 2010, Sultan 2012, Masson 2013, LaRusch_2014). However, some of these patients also carried the variant CFTR c.221G>A (p.Arg74Gln) (Keiles 2006, Masson 2013), and this co-occurring variant is internally classified as a VUS-possibly pathogenic variant for Chronic Pancreatitis Risk. Therefore, these data do not allow clear conclusions about variant significance. A functional study found the variant to be comparable to the wild type in maturation and chloride channel function (Seibert 1997), while another study reported a significantly reduced bicarbonate transport (Choi 2001). According to a later study, other variants that impair bicarbonate permeation may increase the risk for pancreatitis, but not for cystic fibrosis (LaRusch 2014). Six other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as benign, four as likely benign and one laboratory classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000180169 SCV000710897 likely benign not specified 2017-11-02 criteria provided, single submitter clinical testing p.Arg297Gln variant in exon 8 of CFTR: This variant is not expected to have clin ical significance because it has been identified in 2 unaffected individuals in trans with a pathogenic variant (Dorval 1995). This variant has also been report ed in ClinVar (Variation ID 54082) and has been identified in 0.1% (155/126020) of European chromosomes by the Genome Aggregation Database (gnomAD, http://gnoma d.broadinstitute.org; dbSNP rs143486492). Computational prediction tools and con servation analysis suggest that the p.Arg297Gln variant may not impact the prote in, though this information is not predictive enough to rule out pathogenicity. ACMG/AMP Criteria applied: BS2, BP4.
Mendelics RCV000987959 SCV001137471 likely benign Cystic fibrosis 2019-05-28 criteria provided, single submitter clinical testing
Ambry Genetics RCV001018491 SCV001179737 likely benign Inborn genetic diseases 2019-02-09 criteria provided, single submitter clinical testing In silico models in agreement (benign) ;Intact protein function observed by in vitro/ex vivo assays;Seen in conjunction with two deleterious mutations confirmed in trans in symptomatic individuals
Illumina Clinical Services Laboratory,Illumina RCV001165380 SCV001327569 likely benign 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). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
CeGaT Praxis fuer Humangenetik Tuebingen RCV001311300 SCV001501414 uncertain significance not provided 2020-12-01 criteria provided, single submitter clinical testing
Mayo Clinic Laboratories, Mayo Clinic RCV001311300 SCV001714225 uncertain significance not provided 2020-06-10 criteria provided, single submitter clinical testing
GeneDx RCV001311300 SCV001773559 uncertain significance not provided 2019-11-21 criteria provided, single submitter clinical testing Observed in individuals with pancreatitis (Casals 2004, Keiles 2006, Suttton 2010, Sultan 2012); Observed in individuals with cystic fibrosis and/or an abnormal newborn screen (Scotet 2000, Hughes 2001, Scotet 2001, Abou Alaiwa 2014); Published functional studies are inconclusive: reduced bicarbonate:chloride transport ratio with chloride channel function similar to wildtype (Seibert 1997, Choi 2001); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 11788091, 15097853, 7551394, 9305991, 11242048, 11022925, 11288718, 11168024, 24418186, 17003641, 22094894, 20846557, 1284534, 23523379, 20416310, 29589582, 11354633, 23951356, 8818956, 16778595, 8680407, 23514810, 20021716, 25087612, 18456578, 11288708)
Nilou-Genome Lab RCV000987959 SCV001781361 uncertain significance Cystic fibrosis 2021-07-14 criteria provided, single submitter clinical testing
Natera, Inc. RCV000987959 SCV001453954 uncertain significance Cystic fibrosis 2017-11-14 no assertion criteria provided clinical testing

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