ClinVar Miner

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

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001081823 SCV000074982 likely benign Cystic fibrosis 2020-12-02 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp 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 none provided 2020-03-28 criteria provided, single submitter clinical testing The CFTR c.374T>C; p.Ile125Thr variant (rs141723617) is reported in the literature in the heterozygous state in individuals affected with cystic fibrosis or CFTR-related disorders such as bronchiectasis and pancreatitis, but its clinical significance was not determined (Chang 2007, Kilinc 2002, Lee 2003, Nakano 2015, Ngiam 2006). This variant is listed in ClinVar (Variation ID: 53802), and is found in the East Asian population with an allele frequency of 0.96% (192/19944 alleles, including a single homozygote) in the Genome Aggregation Database. The isoleucine at codon 125 is moderately conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is tolerated. However, given the limited clinical and lack of functional data, the significance of the p.Ile125Thr variant is uncertain at this time. References: Chang M et al. Spectrum of mutations and variants/haplotypes of CFTR and genotype-phenotype correlation in idiopathic chronic pancreatitis and controls in Chinese by complete analysis. Clin Genet. 2007; 71(6):530-9. Kilinc MO et al. Highest heterogeneity for cystic fibrosis: 36 mutations account for 75% of all CF chromosomes in Turkish patients. Am J Med Genet. 2002 Dec 1;113(3):250-7. Lee K et al. Mutation analysis of SPINK1 and CFTR gene in Korean patients with alcoholic chronic pancreatitis. Dig Dis Sci. 2005; 50(10):1852-6. Nakano E et al. Targeted next-generation sequencing effectively analyzed the cystic fibrosis transmembrane conductance regulator gene in pancreatitis. Dig Dis Sci. 2015; 60(5):1297-307. Ngiam N et al. Cystic fibrosis transmembrane conductance regulator (CFTR) gene mutations in Asians with chronic pulmonary disease: a pilot study. J Cyst Fibros. 2006; 5(3):159-64.
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.
Mayo Clinic Laboratories, Mayo Clinic RCV001509309 SCV001715935 uncertain significance not provided 2020-08-18 criteria provided, single submitter clinical testing
Nilou-Genome Lab RCV001081823 SCV001821996 uncertain significance Cystic fibrosis 2021-07-22 criteria provided, single submitter clinical testing
Natera, Inc. RCV001081823 SCV001453947 benign Cystic fibrosis 2020-04-16 no assertion criteria provided clinical testing

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