ClinVar Miner

Submissions for variant NM_000492.4(CFTR):c.3208C>T (p.Arg1070Trp) (rs202179988)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
PharmGKB RCV000660792 SCV000783031 drug response ivacaftor response - Efficacy 2018-03-23 reviewed by expert panel curation PharmGKB Level of Evidence 1A: Annotation for a variant-drug combination in a CPIC or medical society-endorsed PGx guideline, or implemented at a PGRN site or in another major health system.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000219441 SCV000271348 pathogenic Cystic fibrosis; Congenital bilateral aplasia of vas deferens from CFTR mutation 2015-05-11 criteria provided, single submitter clinical testing The p.Arg1070Trp variant in CFTR has been reported in >20 compound heterozygous individuals (the majority carrying p.Phe508del) primarily affected by milder for ms of CFTR-related disorders (congenital bilateral absence of the vas deferens a nd cystic fibrosis) and more than half of these individuals were reported to hav e normal to low sweat chloride levels (Jezequel 1995, Feldmann 2003, Krasnov 200 8, Pelletier 2010, de Prada Merino 2010, Steiner 2011, Sosnay 2013). In addition , this variant has been identified in 4/66100 of European chromosomes and 1/1034 0 African chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.bro adinstitute.org; dbSNP rs202179988). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessiv e carrier frequency. In vitro functional studies provide some evidence that the p.Arg1070Trp variant may impact protein function (Krasnov 2008, Sosnay 2013, Van Goor 2014). However, these types of assays may not accurately represent biologi cal function. In summary, this variant meets our criteria to be classified as pa thogenic for CTFR-related disorders including CBAVD and cystic fibrosis in an au tosomal recessive manner (http://www.partners.org/personalizedmedicine/LMM) base d upon multiple co-occurrences with pathogenic variants and its low frequency in the general population.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000507471 SCV000601093 likely pathogenic not provided 2016-09-29 criteria provided, single submitter clinical testing
Mendelics RCV000757802 SCV000886268 pathogenic Cystic fibrosis 2018-11-05 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000757802 SCV000916186 pathogenic Cystic fibrosis 2018-11-02 criteria provided, single submitter clinical testing The CFTR c.3208C>T (p.Arg1070Trp) missense variant is well described in the literature as a mild or intermediate variant and is reported to have varying clinical consequences including pancreatic sufficient cystic fibrosis (CF) and congenital bilateral absence of the vas deferens (CBAVD). The p.Arg1070Trp variant has been identified in a compound heterozygous state in at least four studies in six individuals with CBAVD (Jezequel et al. 1995; Mickle et al. 2000; Jezequel et al. 2000; Steiner et al. 2011). The variant has also been reported as part of a complex allele in a compound heterozygous state with a pathogenic splice site variant in a proband with CF (de Prada Merino et al. 2010). Functional studies by Van Goor et al. (2014) demonstrated the p.Arg1070Trp variant resulted in 8% of wild type levels of chloride ion transport. The p.Arg1070Trp variant is reported in the CFTR2 mutation database in a total of 13 alleles (Sosnay et al. 2013), and is described as a "mutation of varying clinical consequence." Incomplete penetrance is documented in association with the p.Arg1070Trp variant; not all individuals who carry this variant along with a second disease-causing CFTR variant in trans will display symptoms of a CFTR-related disorder (CFTR2 2016). Control data are unavailable for this variant, which is reported at a frequency of 0.000125 in the African population of the Genome Aggregation Database. Based on the collective evidence, the p.Arg1070Trp variant is classified as pathogenic for CFTR-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000757802 SCV000917197 likely pathogenic Cystic fibrosis 2021-03-04 criteria provided, single submitter clinical testing Variant summary: CFTR c.3208C>T (p.Arg1070Trp) results in a non-conservative amino acid change located in the ABC transporter type 1, transmembrane domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.8e-05 in 250962 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in CFTR causing CFTR-Related Diseases (4.8e-05 vs 0.013), allowing no conclusion about variant significance. c.3208C>T has been reported in the literature in compound heterozygosity with another pathogenic variant in multiple individuals affected with CFTR-Related Diseases, primarily CBAVD (e.g. Jezequel_1995, Steiner_2011) and Non-Classic Cystic Fibrosis (e.g. McGinnis_2005, Sosnay_2013). These data indicate that the variant is likely to be associated with disease. A worldwide survey of patients with the p.Arg1070Trp variant identified 24 patients with complete clinical data (21 of which had the common pathogenic variant p.Phe508del or another severe CFTR mutation), and included 15 patients with CBAVD, 9 with non-classic CF, and 1 with classic CF phenotypes (Krasnov_2008). A second large survey that collected data from CF registries and clinics in the US and Europe reported the variant in a total of 13 CF alleles, but indicated that only 20% of the individuals were pancreatic-insufficient, with a mean lung function of 93.7%. 16.7% of these patients had tested positive for Pseudomonas (Sosnay_2013). Collectively, the clinical data on patients with this variant suggests that c.3208C>T is most likely a relatively mild mutation that is most often associated with either pancreatic-sufficient non-classic CF or CBAVD when present in trans with a more severe CFTR mutation. Several functional studies evaluating an impact on protein function have reported conflicting conclusions regarding the effects of this variant. One study reported that chloride channel function in cells expressing the variant was comparable to wild-type (e.g. Mickle_2000), however, it has also been reported that chloride conductance in cells expressing the variant was <10% that of wild-type (e.g. Van Goor_2013, Sosnay_2013). CFTR maturation and the amount of protein expression was 91% and 67.8% of the wild-type as measured in HeLa cells and FRT cells, respectively (Sosnay_2013), and the variant was reported to retain localization to the apical membrane, albeit less efficiently than the wild-type protein (e.g. Krasnov_2008). Eight other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Baylor Genetics RCV000219441 SCV001163177 pathogenic Cystic fibrosis; Congenital bilateral aplasia of vas deferens from CFTR mutation criteria provided, single submitter clinical testing
CFTR-France RCV001009384 SCV001169237 pathogenic Cystic fibrosis; CFTR-related disorders 2018-01-29 criteria provided, single submitter curation when the variant is in trans with another CF-causing variation, can either result in CF or in a CFTR-RD
Ambry Genetics RCV001019230 SCV001180561 pathogenic Inborn genetic diseases 2018-07-24 criteria provided, single submitter clinical testing The p.R1070W pathogenic mutation (also known as c.3208C>T), located in coding exon 20 of the CFTR gene, results from a C to T substitution at nucleotide position 3208. The arginine at codon 1070 is replaced by tryptophan, an amino acid with dissimilar properties. <span style="background-color:initial">In one study, this mutation was identified in conjunction with a second CFTR alteration <span style="background-color:initial">in<span style="background-color:initial"> 24 individuals with pancreatic sufficient cystic fibrosis or <span style="background-color:initial">congenital bilateral absence of the vas deferens (CBAVD) <span style="background-color:initial">(Krasnov KV et al. Hum. Mutat., 2008 Nov;29:1364-72<span style="background-color:initial">). I<span style="background-color:initial">n vitro functional studies showed that cells with this mutation have significantly decreased chloride conductance compared to wild type (Sosnay PR et al. Nat. Genet., 2013 Oct;45:1160-7; Van Goor F et al. J. Cyst. Fibros., 2014 Jan;13:29-36) and <span style="background-color:initial">CFTR protein with this mutation was able to process into mature protein but with decreased efficiency compared to wild-type<span style="background-color:initial"> (Krasnov KV et al. Hum. Mutat., 2008 Nov;29:1364-72<span style="background-color:initial">). The p.R1070W alteration has been reported as a variant of varying clinical consequences (VVCC) (Sosnay PR et al. Nat. Genet. 2013 Oct; 45(10):1160-7; Sosnay PR et al. Pediatr. Clin. North Am. 2016 Aug;63(4):585-98). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Invitae RCV000757802 SCV001580624 pathogenic Cystic fibrosis 2020-10-27 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 1070 of the CFTR protein (p.Arg1070Trp). The arginine residue is moderately conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is present in population databases (rs202179988, ExAC 0.01%). This variant has been reported with a second CFTR variant in individuals affected with congenital bilateral absence of the vas deferens (PMID: 7539342, 21520337, 9598638, 9239681, 18951463, 10875853, 15070876) and cystic fibrosis (PMID: 23974870, 16189704, 18951463, 20880762). It has also been reported in the heterozygous state in individuals affected with chronic pancreatitis (PMID: 27171515, 20460946). ClinVar contains an entry for this variant (Variation ID: 53685). Experimental studies have shown that this missense change impairs CFTR maturation, apical membrane insertion, and chloride transport (PMID: 23891399, 18951463). For these reasons, this variant has been classified as Pathogenic.
Counsyl RCV000757802 SCV001132151 likely pathogenic Cystic fibrosis 2018-12-26 no assertion criteria provided clinical testing

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