ClinVar Miner

Submissions for variant NM_000492.3(CFTR):c.2002C>T (p.Arg668Cys) (rs1800100)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000723382 SCV000603020 uncertain significance not provided 2017-06-09 criteria provided, single submitter clinical testing The CFTR c.2002C>T; p.Arg668Cys variant (rs1800100) was first reported in patients diagnosed with cystic fibrosis, but failed to segregate with the disorder (Fanen 1992). It was also found in-cis with another pathogenic variant (Dork 1994). The variant was later identified in multiple patients with bronchiectasis (Pignatti 1995, Ziedalski 2006), chronic pancreatitis (Steiner 2011, El-Seedy 2012, Masson 2013) and congenital bilateral absence of vas deferens (Chillon 1995, Dork 1997, Schrijver 2005, Steiner 2011), often found in-cis with the p.Gly576Ala variant. Functional studies indicate that the p.Arg668Cys variant protein has reduced chloride transport (approximately 50 percent of wildtype) (Sosnay 2013, Van Goor 2014, Salinas 2015). However, the p.Arg668Cys variant has been observed in healthy individuals who have a pathogenic CFTR variant on the other chromosome, though its prevalence in patients with CFTR-related disorders means a mild effect cannot be ruled out (El-Seedy 2012). The variant is listed in ClinVar (Variation ID: 35832), and observed in the general population databases at frequencies of 0.28 percent (14/5008 alleles, 1000 Genomes Project), 0.6 percent (81/13006 alleles, Exome Variant Server), and 0.6 percent (1630/275868 alleles, Genome Aggregation Database). The arginine at residue 668 is highly conserved, and computational algorithms (Mutation Taster, PolyPhen-2, SIFT) predict that the variant has an impact on the protein. Due to the conflicting information regarding this variant, its clinical significance cannot be determined with certainty. References: Chillon M et al. Mutations in the cystic fibrosis gene in patients with congenital absence of the vas deferens. N Engl J Med. 1995. 332(22):1475-80. Dork T et al. Detection of more than 50 different CFTR mutations in a large group of German cystic fibrosis patients. Hum Genet. 1994. 94(5):533-42. Dork T et al. Distinct spectrum of CFTR gene mutations in congenital absence of vas deferens. Hum Genet. 1997. 100(3-4):365-77. El-Seedy A et al. CFTR mutation combinations producing frequent complex alleles with different clinical and functional outcomes. Hum Mutat. 2012. 33(11):1557-65. Fanen P et al. Molecular characterization of cystic fibrosis: 16 novel mutations identified by analysis of the whole cystic fibrosis conductance transmembrane regulator (CFTR) coding regions and splice site junctions. Genomics. 1992. 13(3):770-6. 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. Pignatti P et al. Increased incidence of cystic fibrosis gene mutations in adults with disseminated bronchiectasis. Hum Mol Genet. 1995. 4(4):635-9. Salinas D et al. Benign outcome among positive cystic fibrosis newborn screen children with non-CF-causing variants. J Cyst Fibros. 2015. 14(6):714-9. Schrijver I et al. Diagnostic testing by CFTR gene mutation analysis in a large group of Hispanics: novel mutations and assessment of a population-specific mutation spectrum. J Mol Diagn. 2005. 7(2):289-99. Sosnay PR et al. Defining the disease liability of variants in the cystic fibrosis transmembrane conductance regulator gene. Nat Genet. 2013. 45(10):1160-7. 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. Van Goor F et al. Effect of ivacaftor on CFTR forms with missense mutations associated with defects in protein processing or function. J Cyst Fibros. 2014. 13(1):29-36. Ziedalski T et al. Prospective analysis of cystic fibrosis transmembrane regulator mutations in adults with bronchiectasis or pulmonary nontuberculous mycobacterial infection. Chest. 2006. 130(4):995-1002.
Clinical Molecular Genetics Laboratory,Johns Hopkins All Children's Hospital RCV000582625 SCV000692325 uncertain significance Chronic sinusitis 2015-05-14 no assertion criteria provided clinical testing c.1727G>C and c.2002C>T found in cis
Clinical Molecular Genetics Laboratory,Johns Hopkins All Children's Hospital RCV000583839 SCV000692326 uncertain significance Lung disease, non-specific 2015-05-14 no assertion criteria provided clinical testing c.1727G>C and c.2002C>T found in cis
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000723382 SCV000110851 uncertain significance not provided 2018-07-27 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000515296 SCV000611382 uncertain significance Bronchiectasis with or without elevated sweat chloride 1; Cystic fibrosis; Hereditary pancreatitis; Congenital bilateral absence of the vas deferens 2017-05-23 criteria provided, single submitter clinical testing
GeneDx RCV000723382 SCV000329249 uncertain significance not provided 2018-06-06 criteria provided, single submitter clinical testing The R668C variant has also been reported, predominantly as a complex allele in cis with G576A, in multiple patients with non-classical cystic fibrosis, including late-onset pulmonary disease, congenital bilateral absence of the vas deferens (CBAVD), or idiopathic pancreatitis (Chillón et al., 1995; Steiner et al., 2011; El-Seedy et al., 2012). In vitro functional studies of R668C demonstrated a mild but significant reduction of CFTR chloride conductance with a significant response to the drug Ivacaftor (Van Goor et al., 2014; El-Seedy et al., 2012). The R668C variant is a non-conservative amino acid substitution, which occurs at a position that is conserved across species. However, the R668C variant is observed in 609/65,954 alleles (0.9%) alleles from individuals of European (non-Finnish) background including one homozygous individual in the ExAC dataset (Lek et al., 2016). In addition, the R668C variant has been reported in multiple unaffected individuals and likely exhibits incomplete penetrance (Steiner et al., 2011; Sosnay et al., 2013). We interpret R668C as a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000155473 SCV000696881 likely benign not specified 2016-05-23 criteria provided, single submitter clinical testing Variant Summary: The variant CFTR c.2002C>T (p.Arg668Cys) occurs at a non-conserved position. 5/5 in silico tools predict a damaging outcome for this variant. It is frequently observed with other sequence changes (with p.Asp443Tyr and p.Gly576Ala) on the same chromosome, thereby creating complex alleles that are of clinical significance to CFTR-related disorders including non-classic CF. Recently, p.R668C has been deemed non-penetrant due to its presence in the non-transmitted allele of carrier fathers (29/4124 alleles = 0.7%) of CF-affected childs at a frequency similar to that observed in the general population (0.4-0.9%) and an approximately 10 fold lower frequency of occurrence in individuals with cystic fibrosis listed in CFTR2 database (49/70,777 alleles = 0.07%) as would be expected for a non-penetrant CFTR allele (Sosnay et al 2013). These findings are consistent with the observed allele frequency of 766/124616 (1/163; 0.61%), which is lower than the maximal expected allele frequency of 1/77 (1.23%) for a pathogenic CFTR variant associated with classic CF. Furthermore, the observed allele frequency in the ExAC database of 0.61% with one homozygous occurrence is similar to the frequency of the most common CF-causing variant, deltaF508 (0.68% without a homozygous occurrence). This supports the notion that this missense variant is likely not CF-causing since R668C has been reported in very few CF patients. The baseline chloride transport of R668C was shown to be intermediate of normal CFTR (El-Seedy et al 2012, Van Goor et al 2013, Sosnay et al 2013), but the in vivo consequence of this level of activity is unknown. But the variant p.R668C does not affect glycosylation and subcellular localization (El-Seedy et al 2012, Sosnay et al 2013). This variant has been reported to alter the splicing properties of other variants which include p.D565G and p.G576A, but does not appear to have a significant impact on splicing when in isolation (Pagani et al 2003). Contrary to the classification provided by two labs in ClinVar (Emory Genetics and LMM as VUS), the CFTR2 database states that this variant does not cause CF in combination with other CF-causing mutations. Although this variant in isolation is not CF-causing, it could still represent as a risk variant for CFTR-RD. Based on the currently available information, this variant is classified as a Probable Normal Variant (i.e. likely benign).
Invitae RCV000029490 SCV000254589 benign Cystic fibrosis 2017-12-27 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000155473 SCV000205165 uncertain significance not specified 2015-07-31 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Benign. The p.Arg668Cys var iant in CFTR has been reported in >50 compound heterozygous individuals with var ying clinical diagnoses, including congenital bilateral absence of the van defer ens (CBAVD), diffuse bronchiectasis, idiopathic pancreatitis, and cystic fibrosi s (Chillon 1995, Dork 1997, Sosnay 2013, El-Seedy 2012); however most of these i ndividuals carried one or more CFTR variants in cis with this variant. This vari ant has been identified in 0.92% (609/65954) Europeans by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs1800098). The carrier frequency of this variant in individuals with CF has reported to be lower than t he carrier frequency in the general population (Sosnay 2013). Computational pred iction tools and evolutionary conservation analysis do not provide strong suppor t for or against an impact to the protein. In summary, while the clinical signif icance of the p.Arg668Cys variant is uncertain, these data suggest that it is m ore likely to be benign.
Mendelics RCV000029490 SCV000886140 uncertain significance Cystic fibrosis 2018-11-05 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000155473 SCV000601064 uncertain significance not specified 2017-05-23 criteria provided, single submitter clinical testing

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