ClinVar Miner

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

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001081823 SCV000074982 likely benign Cystic fibrosis 2019-12-31 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000595646 SCV000696986 likely benign not specified 2020-03-03 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 not significantly higher than expected for a pathogenic variant in CFTR causing Cystic Fibrosis allowing no conclusion about variant significance. c.374T>C has been reported in the literature in sequencing studies of healthy controls and individuals affected with Cystic Fibrosis, pancreatitis of idiopathic, chronic, acute and autoimmume etiologies, and as a VUS reported in settings of carrier screening (example, Kilinc_2002, Chang_2007, Kim_2010, Ngiam_2006, Jang_2013, Nakano_2015, Chang_2015, Lee_2003, DeWachter_2017, Archibald_2017, Xiao_2017, Guan_2018, Schrijver_2016). Specifically, this variant was reported in trans with p.F508del in a female patient of Chinese ethnicity who was reportedly pancreatic sufficient and had sweat chloride of < 60 mmol/L (36mmol/L) (DeWachter_2017). These report(s) do not provide unequivocal conclusions about association of the variant with Cystic Fibrosis. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (likely benign, n=2; VUS, n=1). We have followed this variant for 5 years since its initial evaluation at our laboratory and to our knowledge have not ascertained any convincing evidence that supports a pathogenic outcome. Based on the evidence outlined above, the variant was re-classified as likely benign.
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
Ambry Genetics RCV001021042 SCV001182605 likely benign Inborn genetic diseases 2018-04-18 criteria provided, single submitter clinical testing In silico models in agreement (benign) ;Sub-population frequency in support of benign classification (not ava blue, manual h-w)
Illumina Clinical Services Laboratory,Illumina RCV001163272 SCV001325295 uncertain significance CFTR-related disorders 2017-04-27 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). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

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