ClinVar Miner

Submissions for variant NM_000492.3(CFTR):c.3659C>T (p.Thr1220Ile) (rs1800123)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000507411 SCV000603027 uncertain significance not specified 2017-01-05 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000589624 SCV000696979 uncertain significance not provided 2016-02-26 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000589624 SCV000860875 uncertain significance not provided 2018-04-19 criteria provided, single submitter clinical testing
Ambry Genetics RCV001020816 SCV001182346 uncertain significance Inborn genetic diseases 2019-07-16 criteria provided, single submitter clinical testing The p.T1220I variant (also known as c.3659C>T), located in coding exon 22 of the CFTR gene, results from a C to T substitution at nucleotide position 3659. The threonine at codon 1220 is replaced by isoleucine, an amino acid with similar properties. This alteration was reported in a 60 year old woman with a 10 year history of chronic lung disease (Ghanem N et al. Genomics. 1994;21(2):434-6) and in a 13 year old with gastrointestinal problems, elevated sweat chloride, and pancreatic sufficiency (Onay T et al. Hum Genet. 1998;102(2):224-30); however, a second disease-causing variant in trans was not described in either case. In addition, this alteration was reported in a child with pancreatitis who was also heterozygous for disease-causing variants in PRSS1 and SPINK1 (Xiao Y et al. J. Pediatr., 2017 12;191:158-163.e3). This amino acid position is poorly conserved in available vertebrate species, and I is the reference amino acid in other vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae RCV000007635 SCV001417932 uncertain significance Cystic fibrosis 2020-10-29 criteria provided, single submitter clinical testing This sequence change replaces threonine with isoleucine at codon 1220 of the CFTR protein (p.Thr1220Ile). The threonine residue is weakly conserved and there is a moderate physicochemical difference between threonine and isoleucine. This variant is present in population databases (rs1800123, ExAC 0.09%). This variant has been observed in individual(s) with clinical features of CFTR-related conditions (PMID: 7522211, 29173301, 9521595, 9272738). ClinVar contains an entry for this variant (Variation ID: 7214). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: Tolerated; PolyPhen-2: Benign; Align-GVGD: Class C0. The isoleucine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Nilou-Genome Lab RCV000007635 SCV001781369 uncertain significance Cystic fibrosis 2021-07-14 criteria provided, single submitter clinical testing
OMIM RCV000007635 SCV000027836 pathogenic Cystic fibrosis 1994-05-15 no assertion criteria provided literature only
Natera, Inc. RCV000007635 SCV001460114 uncertain significance Cystic fibrosis 2018-04-28 no assertion criteria provided clinical testing

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