ClinVar Miner

Submissions for variant NM_000492.3(CFTR):c.374T>C (p.Ile125Thr) (rs141723617)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000586603 SCV000074982 likely benign not provided 2019-02-04 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000595646 SCV000696986 uncertain significance not specified 2019-06-27 criteria provided, single submitter clinical testing Variant summary: CFTR c.374T>C (p.Ile125Thr) results in a non-conservative amino acid change located in the ABC transporter type 1, transmembrane domain (IPR011527) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00074 in 252614 control chromosomes, predominantly at a frequency of 0.0094 within the East Asian subpopulation in the gnomAD database, including 1 homozygote. This frequency is almost equal to the estimated maximal expected allele frequency of a pathogenic variant in CFTR causing Cystic Fibrosis (0.00094 vs 0.013) suggesting this may be a benign polymorphism found primarily in the populations of East Asian origin. The variant, c.374T>C, has been reported in the literature in individuals mainly of East Asian origin affected with cystic fibrosis, chronic pancreatitis, idiopathic bronchiectasis but also in healthy controls (Chang_2007, Guan_2018, Jang_2013, Kilinc_2002, Lee_2003, Nakano_2015, Ngiam_2006, Xiao_2017). These reports do not provide unequivocal conclusions about association of the variant with Cystic Fibrosis. Nakano et al (2015) reported the variant co-occurring with a pathogenic variant in SPINK1 gene (IVS3+2T>C (c.194+2T>C)) in one chronic pancreatitis patient. Furthermore, De Wachter et al (2017) reported the variant in trans with F508del in a CF female patient that was pancreatic sufficient and had sweat chloride of < 60 mmol/L (36mmol/L). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (1x) and twice as likely benign. Based on the evidence outlined above, the variant was classified as uncertain significance until additional information of clinical or functional importance becomes available.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000595646 SCV000706922 likely benign not specified 2017-03-13 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000586603 SCV000885191 uncertain significance not provided 2017-10-22 criteria provided, single submitter clinical testing

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