ClinVar Miner

Submissions for variant NM_000492.4(CFTR):c.220C>T (p.Arg74Trp) (rs115545701)

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Total submissions: 17
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
PharmGKB RCV000660770 SCV000783009 drug response ivacaftor response - Efficacy 2018-03-22 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.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000224532 SCV000228891 likely pathogenic not provided 2018-08-03 criteria provided, single submitter clinical testing
Center for Pediatric Genomic Medicine,Children's Mercy Hospital and Clinics RCV000224532 SCV000281538 likely pathogenic not provided 2015-03-23 criteria provided, single submitter clinical testing
Invitae RCV000177071 SCV000562311 benign Cystic fibrosis 2020-12-04 criteria provided, single submitter clinical testing
GeneDx RCV000479747 SCV000568547 uncertain significance not specified 2016-06-10 criteria provided, single submitter clinical testing The R74W variant in the CFTR gene has been reported previously as heterozygous in one individual with CF; no other variants in the CFTR gene were identified in this individual (Claustres et al., 1993). Expression studies in FRT cells showed that D1270N transfected cells displayed decreased chloride transport activity compared to wild type cells (Van Goor et al., 2014). However, an earlier functional study in HeLa cells showed that D1270N transfected cells displayed chloride transport kinetics similar to wild type cells (Fanen et al., 1999). The R74W variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position where amino acids with similar properties to Arginine are tolerated across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. We interpret R74W as a variant of uncertain significance.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000224532 SCV000601070 likely pathogenic not provided 2020-04-30 criteria provided, single submitter clinical testing Found in at least one patient with expected phenotype for this gene. Predicted to have a damaging effect on the protein. In multiple individuals, this variant has been seen with a single recessive pathogenic variant in the same gene, suggesting this variant may also be pathogenic. Assessment of experimental evidence regarding the effect of this variant on protein function is inconclusive.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001283171 SCV000602984 pathogenic none provided 2020-06-19 criteria provided, single submitter clinical testing
Counsyl RCV000177071 SCV000800736 uncertain significance Cystic fibrosis 2017-11-25 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000177071 SCV000916174 uncertain significance Cystic fibrosis 2016-07-27 criteria provided, single submitter clinical testing The CFTR c.220C>T (p.Arg74Trp) variant is reported in four studies with clinical information. Claustres et al. (1993) report the variant in a compound heterozygous state in an individual with cystic fibrosis (CF). In this case, the p.Arg74Trp variant is found alone. Luzardo et al. (2002) report one patient with CF carrying the p.Arg74Trp variant as part of the complex allele p.[R74W+D1270N] in a heterozygous state. Claustres et al. (2004) report three patients with congenital absence of the vas deferens (CBAVD) carrying the complex allele p.[R74W+p.D1270N+p.V201M]. They also report two non-CF or asymptomatic patients carrying the p.[R74W+D1270N] complex allele in a heterozygous state and one CF patient with the p.[R74W+D1270N] complex allele in a compound heterozygous state with another missense variant. de Prada Merino et al. (2010) report the p.Arg74Trp variant in an individual with CF in a compound heterozygous state as part of the complex allele p.[R74W+R1070W+D1270N]. Control data are unavailable for this variant, which is reported at a frequency of 0.03540 in the Mandinka in the Gambia population of the 1000 Genomes Project. The evidence for this variant alone is limited. The p.Arg74Trp variant is therefore classified as a variant of unknown significance but suspicious for pathogenicity for CFTR-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000479747 SCV000967179 likely benign not specified 2018-07-06 criteria provided, single submitter clinical testing The p.Arg74Trp variant in CFTR has been reported as a complex allele (p.[Arg74Tr p;Asp1270Asn] or p.[Arg74Trp;Val201Met;Asp1270Asn]) in several individuals with CFTR-related conditions (Aguiano 1992, Casals 1995, Fanen 1999, Padoa 1999, Ravn ik-Glavac 2000, Luzardo 2002, Girodon 2002, Masson 2013, Sosnay 2013, Terlizzi 2 017, Behar 2017, Claustres 20004, Brugnon 2008, de Prada Merino 2010, Steiner 20 11). However, it has also been reported in 1 unaffected child who carried the p. [Arg74Trp;Asp1270Asn] complex allele in trans with a known pathogenic variant (T erlizzi 2017) and in unaffected twins who carried the p.[Arg74Trp;Val201Met;Asp1 270Asn] complex allele in trans with p.Phe508del (Terlizzi 2017, Brugnon 2008). In addition, the p.Arg74Trp variant has been identified in 1.3% (311/24024) of A frican chromosomes, including 3 homozygotes, by the Genome Aggregation Database (gnomAD, An in vitro functional study suggest ed that the p.Arg74Trp variant did not impact protein function (Fanen 1999). Due to its high frequency in GnomAD and observation in unaffecteds, the p.Arg74Trp variant is classified as likely benign. ACMG/AMP Criteria applied: BS1.
Mendelics RCV000177071 SCV001137467 likely benign Cystic fibrosis 2019-05-28 criteria provided, single submitter clinical testing
Ambry Genetics RCV001014796 SCV001175554 uncertain significance Inborn genetic diseases 2019-01-14 criteria provided, single submitter clinical testing The p.R74W variant (also known as c.220C>T) is located in coding exon 3 of the CFTR gene. This variant results from a C to T substitution at nucleotide position 220. The arginine at codon 74 is replaced by tryptophan, an amino acid with dissimilar properties. This variant was initially described as disease-causing in isolation (Claustres M et al.Hum Mol Genet. 1993;2(8):1209-1213), but it was later described as part of a complex allele p.[R74W; D1270N] in two individuals unaffected with cystic fibrosis, one of whom was confirmed to have another mutation in trans (Claustres M et al. BMC Med Genet.2004;5:19). <span style="background-color:initial">This variant is also part of the complex allele p.[R74W; V201M; D1270N] (de Prada Merino A et al. J. Cyst. Fibros. 2010; 9(6):447-9). This complex allele has been identified in the homozygous state and in trans with a pathogenic mutation in CFTR in individuals with CBAVD (Steiner B et al. Hum. Mutat. 2011; 32(8):912-20). <span style="background-color:initial">Furthermore, one functional study found that the p.R74W variant slightly reduced the amount of normal CFTR protein, but the rate of cAMP-responsive anion conductance remained the same as wild-type (Fanen P et al. FEBS Lett.<span style="background-color:initial">1999;452(3):371-374). As such, p.R74W was postulated to be a variant that has no deleterious effect alone, but it may enhance the effect of another alteration when found in cis<span style="background-color:initial">. Based on protein sequence alignment, this amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive<span style="background-color:initial">. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Johns Hopkins Genomics, Johns Hopkins University RCV000177071 SCV001430643 likely pathogenic Cystic fibrosis 2020-06-11 criteria provided, single submitter clinical testing CFTR variant associated with varying clinical consequence. See for phenotype information.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000479747 SCV001432075 uncertain significance not specified 2020-07-23 criteria provided, single submitter clinical testing Variant summary: CFTR c.220C>T (p.Arg74Trp) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0043 in 146102 control chromosomes (in the gnomAD v3 genomes dataset and from publication data), predominantly at a frequency of 0.013 within the African or African-American subpopulation, including 5 homozygotes (gnomAD v3). This frequency is close to the estimated maximal expected allele frequency for a pathogenic variant in CFTR causing Non-classic Cystic Fibrosis phenotype (0.013). However, the c.220C>T (p.Arg74Trp) variant is frequently reported in complex (i.e. in cis) with ether the c.3808G>A (p.Asp1270Asn) and/or c.601G>A (p.Val201Met) variant. The first two variants (i.e. R74W and D1270N) were individually found in control databases at very similar frequencies and allele counts (with the same number of homozygotes) in the African subpopulation. Therefore, although it is not possible to confirm that these variants occurred in the same individuals, it is very likely that the majority of the gnomAD population carried the [R74W;D1270N] complex allele. Independent studies have shown that the R74W variant protein matures fully with complete processing (Fanen_1999), but in vitro assays have also shown a minor impact on splicing (i.e. an increase in exon 3 skipping; Aissat_2013), and a mild impairment on chloride channel function (Van Goor_2013). An extensive amount of published case studies report this variant as part of different complex alleles, e.g. p.[R74W;D1270N], p.[R74W;V201M;D1270N], p.[TG12T5;R74W], in affected individuals mostly associated with CFTR-RD and particularly CBAVD. However, these complex alleles have been also found in trans with a severe CF-causing variant in asymptomatic (i.e. non-CF) individuals (Claustres_2017, Verlingue_1993), thus they may not be sufficient to cause a classic CF disease phenotype. In conclusion, there is no sufficient evidence to suggest that the R74W variant in isolation, when combined with a deleterious variant in trans, is pathogenic. The variant was classified as indeterminate by Sosnay et al (2013), while the CFTR2 database lists the isolated variant as variant of varying clinical consequence. 11 other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (pathogenic/likely pathogenic (4x), uncertain significance (4x) and benign/likely benign (3x)). Based on the evidence outlined above, the variant was classified as uncertain significance.
Baylor Genetics RCV000177071 SCV001482566 pathogenic Cystic fibrosis 2020-06-20 criteria provided, single submitter clinical testing This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
Mayo Clinic Laboratories, Mayo Clinic RCV000224532 SCV001714825 uncertain significance not provided 2021-02-01 criteria provided, single submitter clinical testing
Nilou-Genome Lab RCV000177071 SCV001737208 uncertain significance Cystic fibrosis 2021-05-18 criteria provided, single submitter clinical testing

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