ClinVar Miner

Submissions for variant NM_000492.3(CFTR):c.890G>A (p.Arg297Gln) (rs143486492)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000047282 SCV000075295 benign not provided 2019-03-05 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 RCV000180169 SCV000602982 uncertain significance not specified 2016-12-03 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000180169 SCV000697053 likely benign not specified 2019-04-08 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 0.00064 in 277480 control chromosomes (gnomAD and publications). This frequency is not higher than expected 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. idiopathic chronic pancreatitis (Casals 2004, Keiles 2006, Sutton 2010, Masson 2013, Sultan 2012), asthma (Tzetis 2001) and infertility (Ravnik-Glavac 2001, Gallati 2009). However, these data do not allow clear conclusions about variant significance. In addition, 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). 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, variants that impair bicarbonate permeation may increase the risk for pancreatitis, but not for cystic fibrosis (LaRusch 2014). Four other ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as once benign, twice likely benign and once uncertain significance. Based on the evidence outlined above, the variant ahs been 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

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