ClinVar Miner

Submissions for variant NM_000492.4(CFTR):c.2002C>T (p.Arg668Cys) (rs1800100)

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Total submissions: 18
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000723382 SCV000110851 uncertain significance not provided 2018-07-27 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,; 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.
Invitae RCV000029490 SCV000254589 benign Cystic fibrosis 2020-12-08 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.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000723382 SCV000601064 uncertain significance not provided 2020-04-01 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001283241 SCV000603020 uncertain significance none provided 2020-08-27 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). This variant was also found in cis with another pathogenic variant (Dork 1994), and 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, Grangeia 2018, 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) (Salinas 2015, Sosnay 2013, Van Goor 2014). 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). This variant is listed in ClinVar (Variation ID: 35832), and is observed in the general population with an overall allele frequency of 0.60% (1,683/281,496 alleles, including 6 homozygotes) in the Genome Aggregation Database. The arginine at residue 668 is highly conserved, and computational algorithms (PolyPhen-2, SIFT) predict that this variant is deleterious. 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. Grangeia A et al. Spectrum of CFTR gene sequence variants in a northern Portugal population. Pulmonology. 2018;24(1):3-9. 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.
Fulgent Genetics,Fulgent Genetics RCV000515296 SCV000611382 uncertain significance Bronchiectasis with or without elevated sweat chloride 1; Cystic fibrosis; Hereditary pancreatitis; Congenital bilateral aplasia of vas deferens from CFTR mutation 2017-05-23 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp 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).
Mendelics RCV000029490 SCV000886140 uncertain significance Cystic fibrosis 2018-11-05 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000723382 SCV001155239 pathogenic not provided 2021-03-01 criteria provided, single submitter clinical testing
CFTR-France RCV001009490 SCV001169585 pathogenic CFTR-related disorders 2018-03-26 criteria provided, single submitter curation
Ambry Genetics RCV001014056 SCV001174715 uncertain significance Inborn genetic diseases 2020-06-30 criteria provided, single submitter clinical testing The p.R668C variant (also known as c.2002C>T), located in coding exon 14 of the CFTR gene, results from a C to T substitution at nucleotide position 2002. The arginine at codon 668 is replaced by cysteine, an amino acid with highly dissimilar properties. In one study, p.R668C was reported along with a second CFTR alteration in four men with azoospermia and congenital bilateral absence of the vas deferens (CBAVD) (Chillón M et al. N. Engl. J. Med., 1995 Jun;332:1475-80). One study showed this alteration did not affect splicing but rather the p.G576A, which was found in cis with p.R668C, caused a variable extent of exon skipping (Pagani F et al. Hum. Mol. Genet., 2003 May;12:1111-20). Another functional study reported that this variant decreased but did not abolish chloride channel activity, which is consistent with a moderate phenotype (El-Seedy A et al. Hum. Mutat., 2012 Nov;33:1557-65). This variant has been seen in cis with the p.G576A, p.D443Y, and p.G149R alterations (El-Seedy A et al. Hum. Mutat., 2012 Nov;33:1557-65). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on available evidence to date, this variant is unlikely to be causative of classic CF; however, its contribution to the development of a CFTR-related disorder is uncertain. Thus, this alteration is classified as a variant of unknown significance.
Illumina Clinical Services Laboratory,Illumina RCV001009490 SCV001325749 uncertain significance CFTR-related disorders 2018-02-16 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. 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.
Johns Hopkins Genomics, Johns Hopkins University RCV000029490 SCV001433652 benign Cystic fibrosis 2019-12-08 criteria provided, single submitter clinical testing
Nilou-Genome Lab RCV000029490 SCV001716337 uncertain significance Cystic fibrosis 2021-05-18 criteria provided, single submitter clinical testing
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
Natera, Inc. RCV000029490 SCV001455985 benign Cystic fibrosis 2019-08-05 no assertion criteria provided clinical testing

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