ClinVar Miner

Submissions for variant NM_000492.3(CFTR):c.1054C>T (p.Arg352Trp) (rs193922497)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000506190 SCV000052119 uncertain significance not specified 2021-03-23 criteria provided, single submitter clinical testing Variant summary: CFTR c.1054C>T (p.Arg352Trp) results in a non-conservative amino acid change in 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 0.00041 in 251136 control chromosomes, predominantly at a frequency of 0.003 within the Latino subpopulation in the gnomAD database. This frequency is not significantly higher than expected for a pathogenic variant in CFTR causing CFTR-Related Diseases (0.00041 vs 0.013), allowing no conclusion about variant significance. c.1054C>T has been reported in the literature in both asymptomatic individuals and subjects diagnosed with multiple CFTR-related phenotypes, including congenital bilateral absence of the vas deferens (CBAVD) and cystic fibrosis (CF). The variant has been reported in compound heterozygosity with the severe pathogenic variant p.Phe508del in individuals diagnosed with CBAVD (e.g. Schwarz_2009, Picci_2010) and in patients followed after a positive newborn screening test, but whom did not meet diagnostic criteria for a diagnosis of CF (e.g. Lilley_2010, Catellani_2016). These data suggest that the variant could be a "mild" mutation, which when combined with a more severe mutation can contribute to less severe CFTR-related phenotypes. c.1054C>T has also been reported in multiple CF patients, however without a second mutation and/or other clinical details available (e.g. Kavanakis_2003, Schrijver_2005, Ciminelli_2007, Giusti_2007, Kharazzi_2015). These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence indicating that the variant, when expressed in-vitro in combination with the p.Phe508del mutation, results in approximately 12% of normal CFTR activity (e.g. McCague_2019). In addition, other functional studies investigating the Arg352 residue have reported that this region is important for stabilizing the channel's tertiary structure and predict that mutations in this amino acid may have a functional impact on the protein (e.g. Guinamard_1999, Cui_2008). A different amino acid substitution at this residue, p.Arg352Gln, has been classified by our laboratory as pathogenic. The CFTR2 database reports that this variant has varying consequences and that when combined with another CF-causing variant, some patients have CF, while others do not. Five other ClinVar submitters (evaluation after 2014) cite the variant with conflicting assessments (likely benign, n=1; VUS, n=3; likely pathogenic, n=1). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
Invitae RCV000029469 SCV000074226 likely benign Cystic fibrosis 2020-11-25 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000727191 SCV000601037 uncertain significance not provided 2019-10-31 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000506190 SCV000603070 likely pathogenic not specified 2018-12-10 criteria provided, single submitter clinical testing The CFTR c.1054C>T; p.Arg352Trp variant (rs193922497) is reported in individuals with cystic fibrosis (CF) (Schrijver 2005), mildly elevated sweat chloride (McGinniss 2005), and congenital absence of the vas deferens (CBAVD) (Picci 2010). In an individual with CBAVD, this variant was reported in trans to the pathogenic p.Phe508del variant (Picci 2010). Further, in testing performed at ARUP Laboratories, the p.Arg352Trp variant has been observed in multiple individuals with CFTR-related disorders that carry a second pathogenic variant, though affected individuals primarily exhibit mild forms of disease instead of classic CF. This variant is reported in ClinVar (Variation ID: 35816) and it is found in the Latino population with an allele frequency of 0.3% (105/35414 alleles) in the Genome Aggregation Database. The arginine at residue 352 is highly conserved, computational algorithms (PolyPhen-2, SIFT) predict that the variant is deleterious, and functional analyses report chloride channel activity of 11% of wildtype (CFTR2 database). Additionally, another variant in the same codon, p.Arg352Gln, is considered pathogenic (Sosnay 2013). Based on available information, the variant is classified as likely pathogenic. References: CFTR2 database: McGinniss M et al. Extensive sequencing of the CFTR gene: lessons learned from the first 157 patient samples. Hum Genet. 2005 Dec; 118(3-4):331-8. Picci L et al. Identification of a D579G homozygote cystic fibrosis patient with pancreatic sufficiency and minor lung involvement. Hum Mutat. 1999; 13(2):173. 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 P et al. Defining the disease liability of variants in the cystic fibrosis transmembrane conductance regulator gene. Nat Genet. 2013; 45(10):1160-7.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000727191 SCV000706515 uncertain significance not provided 2017-03-08 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000029469 SCV000916179 uncertain significance Cystic fibrosis 2018-11-06 criteria provided, single submitter clinical testing The CFTR c.1054C>T (p.Arg352Trp) variant is a missense variant that has been reported in at least four studies, in which it is found in a compound heterozygous state with a second variant in four individuals, including in one individual with congenital bilateral absence of the vas deferens and in three newborns who underwent additional screening for cystic fibrosis (CF) following abnormal newborn screening for this condition (McGinniss et al. 2005; Soultan et al. 2008; Lilley et al. 2010; Picci et al. 2010). Two of the newborns were found to carry the p.Arg352Trp variant in cis with another missense variant on one allele and a classic CF variant on the other allele. The CF status of these newborns is not known. Control data are unavailable for this variant, which is reported at a frequency of 0.004764 in the Latino population of the Exome Aggregation Consortium. The evidence for this variant is limited. The p.Arg352Trp 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.
Nilou-Genome Lab RCV000029469 SCV001822035 uncertain significance Cystic fibrosis 2021-07-22 criteria provided, single submitter clinical testing

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