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

gnomAD frequency: 0.00625  dbSNP: rs1800100

Total submissions: 25

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000723382	SCV000110851	uncertain significance	not provided	2018-07-27	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham 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.
Invitae	RCV000029490	SCV000254589	benign	Cystic fibrosis	2024-01-31	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	2022-12-28	criteria provided, single submitter	clinical testing	In the published literature, it has been identified alone and with other variants in individuals affected with cystic fibrosis (CF) or suspected of it (PMID: 15858154 (2005), 24586523 (2014), 26500004 (2016), 28603918 (2017), 29504914 (2018)), chronic obstructive pulmonary disease (COPD) (PMID: 34996830 (2022)), congenital bilateral absence of the vas deferens (CBAVD) or infertility (PMID: 7529962 (1995), 9272157 (1997), 28603918 (2017), 32357917 (2020), 33374015 (2020), 34145097 (2020)), pancreatitis (PMID: 19812525 (2010), 22427236 (2013), 25033378 (2014), 27264265 (2016), 33097431 (2020), 34974990 (2021)), bronchiectasis (PMID: 20167849 (2010), 25797027 (2015), 30845638 (2019)), pediatric cholestasis (PMID: 35626323 (2022)), fetal bowel anomaly (PMID: 33946859 (2021)), and adrenal insufficiency (PMID: 25060775 (2015)). The variant has been identified also in healthy individuals (PMID: 25033378 (2014), 25797027 (2015)). Functional studies show the variant retains approximately 20-60% of the wild-type chloride conductance (PMID: 22678879 (2012), 23974870 (2013), 35418593 (2022)). In addition, splicing studies in the published literature demonstrate that the variant causes aberrant splicing and reduced levels of normal CFTR mRNA (PMID: 25797027 (2015)). When in cis with c.1727G>C (p.Gly576Ala), the variant significantly worsens a splicing defect that causes exon 13 (legacy exon 12) skipping (PMID: 12719375 (2003), 22678879 (2012), 23891399 (2014), 25797027 (2015)). Although the variant alone does not cause classical CF, the threshold of chloride conductance required for normal function is very low and the variant has been associated with CFTR-related disease (PMID: 22678879 (2012), 23891399 (2014)).
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000723382	SCV000603020	uncertain significance	not provided	2023-11-10	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 analyses predict that this variant is deleterious (REVEL: 0.701). Due to conflicting information, the clinical significance of the p.Arg668Cys variant is uncertain at this time. 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. PMID: 7739684. 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. PMID: 7525450. Dork T et al. Distinct spectrum of CFTR gene mutations in congenital absence of vas deferens. Hum Genet. 1997. 100(3-4):365-77. PMID: 9272157. 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. PMID: 22678879. 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. PMID: 1379210. Grangeia A et al. Spectrum of CFTR gene sequence variants in a northern Portugal population. Pulmonology. 2018;24(1):3-9. PMID: 29589582. 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. PMID: 23951356. Pignatti P et al. Increased incidence of cystic fibrosis gene mutations in adults with disseminated bronchiectasis. Hum Mol Genet. 1995. 4(4):635-9. PMID: 7543317. 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. PMID: 25824995. 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. PMID: 15858154. 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. PMID: 23974870. 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. PMID: 21520337. 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. PMID: 23891399. 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. PMID: 17035430.
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	benign	Cystic fibrosis	2023-08-22	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000723382	SCV001155239	pathogenic	not provided	2024-04-01	criteria provided, single submitter	clinical testing	CFTR: PM3:Very Strong, PM2, PP3
CFTR-France	RCV001009490	SCV001169585	pathogenic	CFTR-related disorder	2018-03-26	criteria provided, single submitter	curation
Ambry Genetics	RCV000029490	SCV001174715	uncertain significance	Cystic fibrosis	2022-06-30	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 Laboratory Services, Illumina	RCV001009490	SCV001325749	uncertain significance	CFTR-related disorder	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
Genome-Nilou Lab	RCV000029490	SCV001716337	uncertain significance	Cystic fibrosis	2021-05-18	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV000029490	SCV002507370	benign	Cystic fibrosis	2020-09-16	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV002256005	SCV002529686	likely benign	Hereditary pancreatitis	2020-12-08	criteria provided, single submitter	curation
Revvity Omics, Revvity	RCV000723382	SCV003831651	uncertain significance	not provided	2023-07-06	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV001009490	SCV004114637	uncertain significance	CFTR-related disorder	2023-10-11	criteria provided, single submitter	clinical testing	The CFTR c.2002C>T variant is predicted to result in the amino acid substitution p.Arg668Cys. Both the c.1727G>C (p.Gly576Ala) and c.2002C>T (p.Arg668Cys) variants individually are found with global minor allele frequencies of >0.5%, including several homozygotes (gnomad.broadinstitute.org). Additionally, these two variants individually have been classified as non-CFTR disease-causing in a separate study (see supplemental table 2 in Sosnay et al. 2013. PubMed ID: 23974870). When these variants are present on the same allele, designated as c.[1727G>C, 2002C>T], this complex allele has been reported in patients with pancreatitis and other CFTR-related disorders, including pulmonary disease and congenital bilateral absence of the vas deferens (see for example Gallati et al. 2009. PubMed ID: 20021716; Masson et al. 2013. PubMed ID: 23951356; El-Seedy et al. 2012. PubMed ID: 22678879). Functional studies of the c.[1727G>C; 2002C>T] variant in HeLa cells showed no impairment of CFTR glycosylation or membrane localization, but decreased chloride channel activity (El-Seedy et al. 2012. PubMed ID: 22678879). Due to conflicting findings, the clinical significance of the c.1727G>C and c.2002C>T variants is currently uncertain.
Genetics and Molecular Pathology, SA Pathology	RCV000029490	SCV004175326	uncertain significance	Cystic fibrosis	2023-03-27	criteria provided, single submitter	clinical testing	The CFTR c.2002C>T variant is classified as a VARIANT OF UNCERTAIN SIGNIFICANCE (BS2, PS3_Supporting, PP3) The CFTR c.2002C>T variant is a single nucleotide change in exon 14/27 of the CFTR gene, which is predicted to change the amino acid arginine at position 668 in the protein to cysteine. This variant has been observed in a healthy control population at a frequency which is inconsistent with expectations given the high penetrance of this condition under curation (gnomAD 921 HET, 3 homs in 152166 sequenced alleles, highest allele frequency 1%) (BS2). Functional studies have shown that the variant results in reduced chloride transport (PMID:23891399) and may effect splicing (PMID:25797027) (PS3_supporting). Computational predictions support a deleterious effect on the gene or gene product (PP3). The variant has been reported in dbSNP (rs1800100) and as ?disease causing in the HGMD database (CM950247). It has been reported as Conflicting interpretations of pathogenicity by other diagnostic laboratories (ClinVar Variation ID: 35835) and in the CFTR2 database as not cystic fibrosis causing variant but may be associated with a CFTR-related disorder. The variant is frequently observed with other CFTR variants such as p.Asp443Tyr, p.Gly149Arg, p.Gly576Ala, on the same chromosome which are considered complex alleles that are of clinical significance to CFTR-related disorders (PMID:22678879, PMID:7739684). The variant has been observed together with a CFTR disease-causing variant in patients with congenital bilateral absence of vas deferens (CBAVD) (PMID:7739684) as has the complex allele p.Gly149Arg;p.Gly576Ala;p.Arg668Cys (PMID:22678879).
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
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV001009490	SCV002507457	uncertain significance	CFTR-related disorder	2020-09-16	no assertion criteria provided	clinical testing
Zotz-Klimas Genetics Lab, MVZ Zotz Klimas	RCV002256005	SCV004101073	uncertain significance	Hereditary pancreatitis	2023-11-02	no assertion criteria provided	clinical testing